Pharmaceutical formulation comprising one or more fumaric acid esters in an erosion matrix

ABSTRACT

A pharmaceutical formulation comprising an erosion matrix comprising one or more fumaric acid esters as well as one or more rate-controlling agents, wherein erosion of said erosion matrix permits controlled release of said fumaric acid ester(s).

FIELD OF THE INVENTION

The present invention relates to a pharmaceutical formulation comprisingan erosion matrix. More particularly the invention relates to apharmaceutical formulation comprising an erodible matrix comprising oneor more fumaric acid esters as well as one or more rate-controllingagents, wherein erosion of said erosion matrix permits controlled orsustained release of said fumaric acid esters.

BACKGROUND OF THE INVENTION

Psoriasis is a chronic skin disease, with a high percentage of geneticpre-disposition. The disease fluctuates between acute exacerbation andtimes of complete standstill. Patients suffering from psoriasis may beseverely handicapped because of the external characteristics of thedisease. This affects all parts of life, such as the professional careeras well as the personal and private life.

The therapeutic possibilities available until the therapy according tothe invention are limited, in particular for patients with moderate tosevere psoriasis, and many of them provide only a temporary andshort-term improvement, and/or have severe adverse effects/side effects.Since psoriasis has a high recurrence rate, the majority of patientshave to undergo long-term treatment.

Fumaric acid esters have been used for the treatment of moderate tosevere psoriasis for more than 30 years. In 1994 a defined mixture ofdimethyl fumarate and monoethyl fumarate salts was approved inGermany—Fumaderm® initial/Fumaderm®. One enteric coated tablet ofFumaderm® contains the following active ingredients: dimethylfumarate120 mg; ethylhydrogenfumarate, calcium salt 87 mg;ethylhydrogenfumarate, magnesium salt 5 mg; ethylhydrogenfumarate, zinksalt 3 mg, and the following other ingredients: croscarmellose-sodium,talc, magnesium stearate, coloring agents E 171 and E 132, methacrylicacid-methylmethacrylate-copolymer (1:1), methacrylicacid-ethylacrylate-copolymer (1:1), Macrogol 6000, simethicone,povidone, triethyl citrate, microcrystalline cellulose, highly dispersesilicon dioxide [Summary of Product Characteristics, Fumaderm®, versionJanuary 2009]. By today Fumaderm® represents about 66% of allprescriptions for systemic therapy of psoriasis in Germany. However, ahigh frequency of side effects causes some patient discontinuation earlyin treatment. It is contemplated that the gastrointestinal side effectsand flushing can, at least partially, be explained by the releaseproperties of the prescription formulation, leading to high localconcentrations in the intestines.

The present inventors contemplate that an improved treatment regimen maybe obtained by administration of a pharmaceutical composition that isdesigned to deliver the active substance in a controlled manner, i.e. ina manner that is prolonged, sustained, retarded, slow and/or delayedcompared with the commercially available product.

Fumaric acid esters, such as dimethyl fumarate, can be subject todegradation and hydrolysis. It is e.g. known that dimethyl fumarate ismore prone to hydrolysis in an alkaline/less acidic environment, c.f.more acidic environments (Litjens et al, “In vitro pharmacokinetics ofanti-psoriatic fumaric acid esters”, BMC Pharmacology 2004, 4:22). Thus,dimethyl fumarate is considered to be more prone to hydrolysis in thesmall intestine, c.f. the gastric ventricle. In addition to the pHeffect described above, esterases are considered to contribute tohydrolysis of fumaric acid esters.

WO 2006/037342 discloses controlled release pharmaceutical compositionscomprising fumaric acid ester(s) as active substance(s) wherein thecontrolled release profile results in a reduction in GI(gastro-intestinal) related side-effects.

OBJECT OF THE INVENTION

It is an object of embodiments of the invention to provide a controlledor sustained release pharmaceutical formulation, comprising fumaric acidester(s) as active substance(s) which shows reduced GI(gastro-intestinal) related side-effects and/or reduced flushing overthe prior art Fumaderm® formulation. A further object of the presentinvention is to provide a controlled or sustained release pharmaceuticalformulation comprising fumaric acid ester(s) as active substance(s)which has an improved pharmacokinetic profile over prior artformulations. In particular, it is an object of the present invention toprovide a controlled or sustained release pharmaceutical formulationcomprising fumaric acid ester(s) as active substance(s) which shows areduced variability in AUC and/or C_(max) values over prior artcontrolled release formulations. In particular, it is an object of thepresent invention to provide a controlled or sustained releasepharmaceutical formulation comprising fumaric acid ester(s) as activesubstance(s) which shows an adequate relative bioavailability c.f. e.g.the prior art Fumaderm® formulation. Specifically, it is an object ofthe present invention to provide a controlled or sustained releasepharmaceutical formulation comprising fumaric acid ester(s) as activesubstance(s) which shows a reduced variability in AUC and/or Cmax valuesover the prior art Fumaderm® formulation.

SUMMARY OF THE INVENTION

It has been found by the present inventor(s) that a controlled orsustained release of one or more fumaric acid esters may be obtained byan erosion matrix tablet. The prolongation of the release of API can becontrolled with the amount of rate controlling polymer(s) in relation tothe other components and it is contemplated that high localconcentrations of the API can be avoided or reduced.

It has been found that a controlled or sustained release of one or morefumaric acid esters at a pharmaceutically relevant level may be obtainedfrom a —compared to Fumaderm®-small tablet in order to improve patientcompliance, and wherein high local concentrations of the API may beavoided while securing as complete as possible a delivery of the activesubstance within a defined time period after reaching the site ofabsorption, and wherein at the same time a reduced variability, comparedto Fumaderm® may be provided.

It has been found that formulations according to the invention exhibit agood in vitro/in vivo correlation. In an aspect the in vitro/in vivocorrelation is determined by comparing the time to 80% of the fumaricacid ester being released from the formulations in an in vitrodissolution test to the Cmax being measured in vivo after administrationof the formulations.

It is further contemplated by the present inventors that the controlledrelease of the API by erosion of the matrix minimizes or reduces theexposure of API to hydrolysis within the gastrointestinal tract, therebymitigating degradation of the API prior to absorption.

In a first aspect, it is contemplated that it is hereby possible toretain the treatment effect while at the same time substantiallyreducing some or several of the undesired side effects or adverseeffects known from Fumaderm®, or improving tolerability c.f. Fumaderm®.

In another aspect, it is contemplated that it is hereby possible toobtain an improved treatment effect compared to Fumaderm® while at thesame time reducing the undesired side-effects known from said prior artFumaderm® treatment of psoriasis.

In another aspect, it is contemplated that it is hereby possible toobtain an improved treatment effect while at the same time maintainingtolerability c.f. Fumaderm®.

In a further aspect, it is contemplated that it is hereby possible toobtain an improved treatment effect while at the same time improvingtolerability c.f. Fumaderm®.

In a first aspect the present invention relates to a pharmaceuticalformulation in the form of an erosion matrix tablet comprising:

-   -   i) 10% to 80% by weight of one or more fumaric acid esters        selected from di-(C₁-C₅)alkylesters of fumaric acid and        mono-(C₁-C₅)alkylesters of fumaric acid, or a pharmaceutically        acceptable salt thereof, as an active substance; and    -   ii) 1-50% by weight of one or more rate-controlling agents;

wherein erosion of said erosion matrix permits controlled or sustainedrelease of said active substance.

In an aspect, the present invention relates to a pharmaceuticalformulation in the form of an erosion matrix tablet comprising:

-   -   i) 30% to 60% by weight of one or more fumaric acid esters        selected from di-(C₁-C₅)alkylesters of fumaric acid and        mono-(C₁-C₅)alkylesters of fumaric acid, or a pharmaceutically        acceptable salt thereof, as an active substance; and    -   ii) 3-40% by weight of one or more rate-controlling agents;

wherein erosion of said erosion matrix permits controlled or sustainedrelease of said active substance.

In an aspect the present invention relates to a pharmaceuticalformulation in the form of a monolithic erosion matrix tabletcomprising:

-   -   i) 10% to 80% by weight of one or more fumaric acid esters        selected from di-(C₁-C₅)alkylesters of fumaric acid and        mono-(C₁-C₅)alkylesters of fumaric acid, or a pharmaceutically        acceptable salt thereof, as an active substance; and    -   ii) 1-50% by weight of one or more rate-controlling agents;

wherein erosion of said erosion matrix permits controlled or sustainedrelease of said active substance.

In an aspect the present invention relates to a pharmaceuticalformulation in the form of a monolithic erosion matrix tabletcomprising:

-   -   i) 30% to 60% by weight of one or more fumaric acid esters        selected from di-(C₁-C₅)alkylesters of fumaric acid and        mono-(C₁-C₅)alkylesters of fumaric acid, or a pharmaceutically        acceptable salt thereof, as an active substance; and    -   ii) 3-40% by weight of one or more rate-controlling agents;

wherein erosion of said erosion matrix permits controlled or sustainedrelease of said active substance.

In an aspect the present invention relates to a pharmaceuticalformulation in the form of an erosion matrix tablet comprising:

-   -   A) A tablet core comprising:        -   i) 40-60% by weight of one or more fumaric acid esters            selected from di-(C₁-C₅)alkylesters of fumaric acid and            mono-(C₁-C₅)alkylesters of fumaric acid, or a            pharmaceutically acceptable salt thereof, as an active            substance,        -   ii) 4-6% by weight of a rate-controlling agent;        -   iii) 35-55% by weight of a binder;    -   B) an enteric coating in an amount of about 1.5-3.5% by weight        of the core;

wherein erosion of said erosion matrix results in release of the fumaricacid ester—when subjected to an in vitro dissolution test employing 0.1N hydrochloric acid as dissolution medium during the first 2 hours ofthe test and then 0.05 M phosphate buffer pH 6.8 as dissolutionmedium—as follows:

within the first 2 hours after start of the test from about 0% w/w toabout 5% w/w of the fumaric ester contained in the formulation isreleased, and/or

within the first 3 hours after start of the test from about 20% w/w toabout 75% w/w of the fumaric ester contained in the formulation isreleased, and/or

within the first 4 hours after start of the test from about 50% w/w toabout 98% w/w of the fumaric ester contained in the formulation isreleased, and/or

within the first 5 hours after start of the test from about 70% w/w toabout 100% w/w of the total amount of the fumaric acid ester containedin the formulation is released.

In an aspect the present invention relates to a pharmaceuticalformulation in the form of an erosion matrix tablet comprising:

-   -   A) A tablet core comprising:        -   i) 30-60% by weight of one or more fumaric acid esters            selected from di-(C₁-C₅)alkylesters of fumaric acid and            mono-(C₁-C₅)alkylesters of fumaric acid, or a            pharmaceutically acceptable salt thereof, as an active            substance,        -   ii) 3-6% by weight of a rate-controlling agent;        -   iii) 35-65% by weight of a binder;    -   B) an enteric coating in an amount of about 1.5-3.5% by weight        of the core;

wherein erosion of said erosion matrix results in release of the fumaricacid ester—when subjected to an in vitro dissolution test employing 0.1N hydrochloric acid as dissolution medium during the first 2 hours ofthe test and then 0.05 M phosphate buffer pH 6.8 as dissolutionmedium—as follows:

within the first 2 hours after start of the test from about 0% w/w toabout 5% w/w of the fumaric ester contained in the formulation isreleased, and/or

within the first 3 hours after start of the test from about 20% w/w toabout 75% w/w of the fumaric ester contained in the formulation isreleased, and/or

within the first 4 hours after start of the test from about 50% w/w toabout 98% w/w of the fumaric ester contained in the formulation isreleased, and/or

within the first 5 hours after start of the test from about 70% w/w toabout 100% w/w of the total amount of the fumaric acid ester containedin the formulation is released.

In an aspect the present invention relates to a pharmaceuticalformulation in the form of a monolithic erosion matrix tabletcomprising:

-   -   A) A tablet core comprising:        -   i) 40-60% by weight of one or more fumaric acid esters            selected from di-(C₁-C₅)alkylesters of fumaric acid and            mono-(C₁-C₅)alkylesters of fumaric acid, or a            pharmaceutically acceptable salt thereof, as an active            substance,        -   ii) 4-6% by weight of a rate-controlling agent;        -   iii) 35-55% by weight of a binder;    -   B) an enteric coating in an amount of about 1.5-3.5% by weight        of the core;

wherein erosion of said erosion matrix results in release of the fumaricacid ester—when subjected to an in vitro dissolution test employing 0.1N hydrochloric acid as dissolution medium during the first 2 hours ofthe test and then 0.05 M phosphate buffer pH 6.8 as dissolutionmedium—as follows:

within the first 2 hours after start of the test from about 0% w/w toabout 5% w/w of the fumaric ester contained in the formulation isreleased, and/or

within the first 3 hours after start of the test from about 20% w/w toabout 75% w/w of the fumaric ester contained in the formulation isreleased, and/or

within the first 4 hours after start of the test from about 50% w/w toabout 98% w/w of the fumaric ester contained in the formulation isreleased, and/or

within the first 5 hours after start of the test from about 70% w/w toabout 100% w/w of the total amount of the fumaric acid ester containedin the formulation is released.

In an aspect the present invention relates to a pharmaceuticalformulation in the form of a monolithic erosion matrix tabletcomprising:

-   -   A) A tablet core comprising:        -   i) 30-60% by weight of one or more fumaric acid esters            selected from di-(C₁-C₅)alkylesters of fumaric acid and            mono-(C₁-C₅)alkylesters of fumaric acid, or a            pharmaceutically acceptable salt thereof, as an active            substance,        -   ii) 3-6% by weight of a rate-controlling agent;        -   iii) 35-65% by weight of a binder;    -   B) an enteric coating in an amount of about 1.5-3.5% by weight        of the core;

wherein erosion of said erosion matrix results in release of the fumaricacid ester—when subjected to an in vitro dissolution test employing 0.1N hydrochloric acid as dissolution medium during the first 2 hours ofthe test and then 0.05 M phosphate buffer pH 6.8 as dissolutionmedium—as follows:

within the first 2 hours after start of the test from about 0% w/w toabout 5% w/w of the fumaric ester contained in the formulation isreleased, and/or

within the first 3 hours after start of the test from about 20% w/w toabout 75% w/w of the fumaric ester contained in the formulation isreleased, and/or

within the first 4 hours after start of the test from about 50% w/w toabout 98% w/w of the fumaric ester contained in the formulation isreleased, and/or

within the first 5 hours after start of the test from about 70% w/w toabout 100% w/w of the total amount of the fumaric acid ester containedin the formulation is released.

In an aspect the present invention relates to a pharmaceuticalformulation in the form of an erosion matrix tablet comprising:

-   -   A) A tablet core comprising:        -   i) 30-60% by weight of one or more fumaric acid esters            selected from di-(C₁-C₅)alkylesters of fumaric acid and            mono-(C₁-C₅)alkylesters of fumaric acid, or a            pharmaceutically acceptable salt thereof, as an active            substance,        -   ii) 3-6% by weight of a rate-controlling agent;        -   iii) 35-65% by weight of a binder;    -   B) an enteric coating in an amount of about 1.5-3.5% by weight        of the core;

wherein erosion of said erosion matrix results in release of the fumaricacid ester—when subjected to an in vitro dissolution test employing 0.1N hydrochloric acid as dissolution medium during the first 2 hours ofthe test and then 0.05 M phosphate buffer pH 6.8 as dissolutionmedium—as follows:

within the first 2 hours after start of the test from about 0% w/w toless than about 10% w/w of the fumaric ester contained in theformulation is released, and/or

within the first 3 hours after start of the test from about 20% w/w toabout 75% w/w of the fumaric ester contained in the formulation isreleased, and/or

within the first 4 hours after start of the test from about 5⁰% w/w toabout 98% w/w of the fumaric ester contained in the formulation isreleased, and/or

within the first 5 hours after start of the test from about 70% w/w toabout 100% w/w of the total amount of the fumaric acid ester containedin the formulation is released.

In an aspect the present invention relates to a pharmaceuticalformulation in the form of a monolithic erosion matrix tabletcomprising:

-   -   A) A tablet core comprising:        -   i) 30-60% by weight of one or more fumaric acid esters            selected from di-(C₁-C₅)alkylesters of fumaric acid and            mono-(C₁-C₅)alkylesters of fumaric acid, or a            pharmaceutically acceptable salt thereof, as an active            substance,        -   ii) 3-6% by weight of a rate-controlling agent;        -   iii) 35-65% by weight of a binder;    -   B) an enteric coating in an amount of about 1.5-3.5% by weight        of the core;

wherein erosion of said erosion matrix results in release of the fumaricacid ester—when subjected to an in vitro dissolution test employing 0.1N hydrochloric acid as dissolution medium during the first 2 hours ofthe test and then 0.05 M phosphate buffer pH 6.8 as dissolutionmedium—as follows:

within the first 2 hours after start of the test from about 0% w/w toless than about 10% w/w of the fumaric ester contained in theformulation is released, and/or

within the first 3 hours after start of the test from about 20% w/w toabout 75% w/w of the fumaric ester contained in the formulation isreleased, and/or

within the first 4 hours after start of the test from about 5⁰% w/w toabout 98% w/w of the fumaric ester contained in the formulation isreleased, and/or

within the first 5 hours after start of the test from about 70% w/w toabout 100% w/w of the total amount of the fumaric acid ester containedin the formulation is released.

In an aspect the present invention relates to a pharmaceuticalformulation in the form of an erosion matrix tablet comprising:

-   -   A) A tablet core comprising:        -   i) 30-60% by weight of dimethyl fumarate,        -   ii) 3-6% by weight of hydroxypropyl cellulose;        -   iii) 35-65% by weight of lactose;    -   B) an enteric coating in an amount of about 1.5-3.5% by weight        of the core;

wherein erosion of said erosion matrix results in release of thedimethyl fumarate—when subjected to an in vitro dissolution testemploying 0.1 N hydrochloric acid as dissolution medium during the first2 hours of the test and then 0.05 M phosphate buffer pH 6.8 asdissolution medium—as follows:

within the first 2 hours after start of the test from about 0% w/w toabout 5% w/w of the dimethyl fumarate contained in the formulation isreleased, and/or

within the first 3 hours after start of the test from about 20% w/w toabout 75% w/w of the dimethyl fumarate contained in the formulation isreleased, and/or

within the first 4 hours after start of the test from about 50% w/w toabout 98% w/w of the fumaric ester contained in the formulation isreleased, and/or

within the first 5 hours after start of the test from about 70% w/w toabout 100% w/w of the total amount of the dimethyl fumarate contained inthe formulation is released.

In an aspect the present invention relates to a pharmaceuticalformulation in the form of a monolithic erosion matrix tabletcomprising:

-   -   A) A tablet core comprising:        -   i) 30-60% by weight of dimethyl fumarate,        -   ii) 3-6% by weight of hydroxypropyl cellulose;        -   iii) 35-65% by weight of lactose;    -   B) an enteric coating in an amount of about 1.5-3.5% by weight        of the core;

wherein erosion of said erosion matrix results in release of thedimethyl fumarate—when subjected to an in vitro dissolution testemploying 0.1 N hydrochloric acid as dissolution medium during the first2 hours of the test and then 0.05 M phosphate buffer pH 6.8 asdissolution medium—as follows:

within the first 2 hours after start of the test from about 0% w/w toabout 5% w/w of the dimethyl fumarate contained in the formulation isreleased, and/or

within the first 3 hours after start of the test from about 20% w/w toabout 75% w/w of the dimethyl fumarate contained in the formulation isreleased, and/or

within the first 4 hours after start of the test from about 50% w/w toabout 98% w/w of the fumaric ester contained in the formulation isreleased, and/or

within the first 5 hours after start of the test from about 70% w/w toabout 100% w/w of the total amount of the dimethyl fumarate contained inthe formulation is released.

In the present context the term “% by weight” refers to the percentageby weight of each ingredient in the core tablet, thus excluding anyexterior coatings or films.

In another aspect the present invention relates to a method forpreparing the formulation according to the invention, comprising thesteps of:

-   -   a) Dissolving or suspending either one or both of a fumaric acid        ester and a rate-controlling agent in the form of a polymeric        matrix material in water to obtain an aqueous suspension        thereof;    -   b) Spraying said aqueous suspension on granules of a fumaric        acid ester and/or a binder for a period of time sufficient to        obtain a uniform coating thereon;    -   c) Drying the granules obtained;    -   d) Optionally sieving or milling said granules;    -   e) Blending of any pharmaceutically acceptable excipients and        additives in a manner known per se to obtain a tablet        formulation;    -   f) Optionally film or enteric coating of said tablet formulation        in a manner known per se;

wherein any of or all of the above steps are performed at a temperatureto allow a product temperature not exceeding 45° C.

It is known that e.g. dimethyl fumarate may be lost to sublimation, andthe sublimation is more pronounced at higher temperatures.

In some aspects the manufacturing of formulations according to theinvention is carried out at relatively low temperature, to minimize orreduce sublimation, and involving few intermediate steps and minimalinvolvement of non-machine operated steps. These factors contribute tothe manufacturing process being scalable and feasible in a commercialsetting and at a commercial scale. In some aspects it has been foundthat formulations according to the invention can be manufactured atlarger scale, such as at least 15 kg scale, such as at least 20 kgscale, such as at least 30 kg scale.

In another aspect the present invention relates to a method forpreparing the formulation according to the invention, comprising thesteps of:

-   -   a) Dissolving or suspending a rate-controlling agent in the form        of a polymeric matrix material in water to obtain an aqueous        suspension thereof;    -   b) Spraying said aqueous suspension on granules of a fumaric        acid ester for a period of time sufficient to obtain a uniform        coating thereon;    -   c) Drying the granules obtained;    -   d) Optionally sieving or milling said granules;    -   e) Blending of any pharmaceutically acceptable excipients and        additives in a manner known per se to obtain a tablet        formulation;    -   f) Optionally film or enteric coating of said tablet formulation        in a manner known per se;

wherein any of or all of the above steps are performed at a temperatureto allow a product temperature not exceeding 45° C.

In another aspect, the present invention relates to a method forpreparing the formulation according to the invention, comprising thesteps of:

-   -   a) Optionally sieving or milling crystals of fumaric acid ester;    -   b) Blending of said crystals of fumaric acid ester, a        rate-controlling agent in the form of a polymeric matrix        material, and any pharmaceutically acceptable excipients and        additives by direct compression to obtain a tablet formulation;    -   c) Optionally film and/or enteric coating of said tablet        formulation in a manner known per se;

wherein any of or all of the above steps are performed at a temperatureto allow a product temperature not exceeding 45° C.

In another aspect the pharmaceutical formulation according to theinvention is for use for the treatment of psoriasis, psoriaticarthritis, neurodermatitis, inflammatory bowel disease, such as Crohn'sdisease and ulcerative colitis, polyarthritis, multiple sclerosis (MS),juvenile-onset diabetes mellitus, Hashimoto's thyroiditis, Grave'sdisease, SLE (systemic lupus erythematosus), Sjögren's syndrome,Pernicious anemia, Chronic active (lupoid) hepatitis, Rheumatoidarthritis (RA), lupus nephritis, myasthenia gravis, uveitis, refractoryuveitis, vernal conjunctivitis, pemphigus vulgaris, scleroderma, opticneuritis, pain such as radicular pain, pain associated withradiculopathy, neuropathic pain or sciatica/sciatic pain, organtransplantation (prevention of rejection), sarcoidosis, necrobiosislipoidica or granuloma annulare.

Another aspect of the invention is the use of a pharmaceuticalformulation according to the invention for the preparation of amedicament for the treatment of psoriasis, psoriatic arthritis,neurodermatitis, inflammatory bowel disease, such as Crohn's disease andulcerative colitis, polyarthritis, multiple sclerosis (MS),juvenile-onset diabetes mellitus, Hashimoto's thyroiditis, Grave'sdisease, SLE (systemic lupus erythematosus), Sjögren's syndrome,Pernicious anemia, Chronic active (lupoid) hepatitis, Rheumatoidarthritis (RA), lupus nephritis, myasthenia gravis, uveitis, refractoryuveitis, vernal conjunctivitis, pemphigus vulgaris, scleroderma, opticneuritis, pain such as radicular pain, pain associated withradiculopathy, neuropathic pain or sciatica/sciatic pain, organtransplantation (prevention of rejection), sarcoidosis, necrobiosislipoidica or granuloma annulare.

Another aspect of the invention is a method of treating psoriasis,psoriatic arthritis, neurodermatitis, inflammatory bowel disease, suchas Crohn's disease and ulcerative colitis, polyarthritis, multiplesclerosis (MS), juvenile-onset diabetes mellitus, Hashimoto'sthyroiditis, Grave's disease, SLE (systemic lupus erythematosus),Sjögren's syndrome, Pernicious anemia, Chronic active (lupoid)hepatitis, Rheumatoid arthritis (RA), lupus nephritis, myastheniagravis, uveitis, refractory uveitis, vernal conjunctivitis, pemphigusvulgaris, scleroderma, optic neuritis, pain such as radicular pain, painassociated with radiculopathy, neuropathic pain or sciatica/sciaticpain, organ transplantation (prevention of rejection), sarcoidosis,necrobiosis lipoidica or granuloma annulare, which method comprisesadministering orally to a patient in need thereof an effective dosage ofa pharmaceutical formulation according to the invention

LEGENDS TO THE FIGURE

FIG. 1 shows in vitro dissolution profiles at 37° C. using a paddledissolution apparatus at 100 rpm employing 0.1 N hydrochloric acid asdissolution medium during the first 2 hours of the test and thenfollowed by 0.05 M phosphate buffer pH 6.8 as dissolution medium for theremaining test period of film and enteric coated erosion matrix tabletsaccording to the invention as described in Examples 16, 18, 20, and 22.

FIG. 2 shows an in vitro dissolution profile at 37° C. using a paddledissolution apparatus at 100 rpm employing 0.1 N hydrochloric acid asdissolution medium during the first 2 hours of the test and thenfollowed by 0.05 M phosphate buffer pH 6.8 as dissolution medium for theremaining test period of a film coated erosion matrix tablet accordingto the invention as described in Example 23.

DETAILED DISCLOSURE OF THE INVENTION

In the present context the term “API”, which is an abbreviation for“active pharmaceutical ingredient” and the term “active substance” areused interchangeably and refers to the fumaric acid ester(s) that is tobe released from the pharmaceutical formulation according to theinvention.

In the present context, the term “controlled or sustained release” referto the release from a formulation that is designed to release thefumaric acid ester in a prolonged, retarded, slow and/or delayed mannercompared to the release of the commercially available product Fumaderm®,when tested under comparable conditions (e.g. for in vivo studies: doseequivalents, with or without standardized meal etc., or for in vitrostudies: dose equivalents, dissolution test apparatus and workingconditions including e.g. composition, volume and temperature ofdissolution medium employed, rotation speed etc.).

The release in vivo may be tested by measuring the plasma concentrationat predetermined time periods and thereby obtaining a plasmaconcentration versus time profile for the fumaric acid ester in questionor, if relevant, a metabolite thereof. Furthermore, it is contemplatedthat metabolism already takes place within the gastro-intestinal tractor during passage of the gastro-intestinal mucosa, or upon first passagethrough the hepatic circulation. Accordingly, when dimethylfumarate isadministered, the relevant component to search for in the plasma may bethe monomethyl ester and not the dimethylester of fumaric acid.

Other tests may also be used to determine or to give a measure of therelease of the active substance in vivo. Thus, animals (e.g. minipigs,dogs etc.) may be used as a model. The animals receive the compositionsunder investigation and after specified periods of time, blood samplesare collected and the content of the active ingredient (or metabolitethereof, if relevant) is determined in plasma or specific organs orextracted from the intestinal contents. Another test involves the use ofa specific segment of an animal or human intestine. The segment isplaced in a suitable apparatus containing two compartments (a donor anda receiver) separated by the segment, and the composition underinvestigation is placed in a suitable medium in one compartment (thedonor compartment). The composition will release the active substancethat subsequently is transported across the intestinal segment.

Accordingly, at suitable time intervals, the concentration of the activesubstance (or, if relevant, the metabolite) is measured in the receivercompartment.

A person skilled in the art will be able to adapt the above-mentionedmethod to the specific composition.

With respect to in vitro methods, well-established methods areavailable, especially methods described by official monographs like e.g.United States Pharmacopeia (USP) or the European Pharmacopoeia. A personskilled in the art will know which method to choose and how to selectthe specific conditions to carry out the in vitro test. For instance,the USP prescribes in vitro tests be carried out at 37+/−1.0 such as37+/−0.5 degrees Celsius/Centigrade. In one aspect, a suitabledissolution test is one, wherein the dissolution profile is determinedas described in the United States Pharmacopoeia at 37° C. using a paddledissolution apparatus at 100 rpm employing 0.1 N hydrochloric acid asdissolution medium during the first 2 hours of the test and thenfollowed by 0.05 M phosphate buffer pH 6.8 as dissolution medium for theremaining test period. A person skilled in the art will know how toadjust the conditions applied, e.g. temperature, pH, paddle speed,duration etc. In a further aspect, the in vitro dissolution testing iscarried out as follows: A USP apparatus II (paddles) with 1 litrevessels is used. Bath temperature is set to 37° C.±0.5° C. and paddlespeed to 100 rpm. One tablet is placed in one vessel containing 750 ml0.1N HCl (pH 1.2) over 2 h. After that the pH is changed to 6.8 byadding 220 ml 0.2 M sodium phosphate buffer. 1.5 ml samples are taken ateach sampling time point and analyzed by HPLC for DMF. The HPLCparameters are set as follows: Column: Phenomenex Luna C18, 50×4.6 mm, 3μm; column oven temperature 30° C.: mobile phase: Methanol:20 mMphosphate buffer pH 3.0 (35:65 V/V), inject volume: 5 μl, Flow rate: 0.8ml/min, Detector wavelength: 210 nm, run time 5 min, DMF retention time3.5 min.

In the present context, the term “relative bioavailability” refers to acomparison of the amount of drug absorbed (expressed as area under thecurve (AUC)) after administration of two different formulations orreference product. In the present context, the amount of drug absorbed,expressed as AUC, can be detected in the form of the actual drugadministered, or as a metabolite thereof. The relative bioavailabiltycan be expressed as a percentage of a reference AUC, i.e. AUC %.

In the present context the term “variability” refers to the variabilityof PK parameters (e.g. Cmax and AUC) after administration of apharmaceutical formulation or a reference formulation. The variabilitycan be expressed as the coefficient of variation (CV) for a PKparameter, i.e. the ratio of the standard deviation to the mean.

In the present context the term “tolerability” refers to the potentialof a drug to be endured by subjects and/or patients. In one aspect,“tolerability” is determined as the potential of a drug to be endured bysubjects and/or patients in early stages of treatment, such as withinthe first three months of start of therapy, such as within the firstmonth of start of therapy, such as within the first two weeks of startof therapy, such as within the first week of start of therapy, such aswithin the first three days of start of therapy, such as within thefirst day of start of therapy, such as after the first dose of thetherapy. A drug with better tolerability produces fewer side effects ina subject and/or patient c.f. a drug with worse tolerability.

In the present context the term “substantial absence of” refers to alevel of less than about 1%, such as less than about 0.5%, such as lessthan about 0.3%, such as about 0.0%.

In the present context the terms “rate-controlling agent” and“rate-controlling agent in the form of a polymeric matrix material” areused interchangeably and refer to an agent that is able to delay/sustainand/or prolong the in vivo and/or in vitro release of the activesubstance.

As mentioned above, the in vivo and/or in vitro release of the activesubstance is prolonged, slow and/or delayed compared with thecommercially available Fumaderm® composition. In the present context,the term “prolonged” is intended to indicate that the active substanceis released during a longer time period than Fumaderm® such as at leastduring a time period that is at least 1.2 times, such as, e.g., at least1.5 times, at least 2 times, at least 3 times, at least 4 times or atleast 5 times greater than that of Fumaderm®. Thus, if e.g. 100% ofdimethylfumarate is released from Fumaderm® tablets 3 hours after thestart of a suitable test, then 100% of dimethylfumarate in a compositionaccording to the invention is released at least 3.6 hours after thestart of a suitable test.

In the present context the term “delayed” is intended to indicate thatthe release of the active substance starts at a later point in timecompared with that of Fumaderm® (such as at 30 min or more later suchas, e.g., 45 min or more later, 1 hour or more later or 1.5 hours ormore later).

In the present context the term “monolithic” refers to consisting of orconstituting a single unit.

The formulation according to the invention is contemplated to provideimproved tolerability, such as fewer and/or less severe gastrointestinal(GI) side-effects, such as fewer and/or less severe redness episodes,such as fewer and/or less severe flushing episodes.

As used in the present invention, a gastrointestinal (GI) side effectmay include, but is not limited to diarrhea, stomach ache, stomach pain,abdominal pain, abdominal cramps, nausea, flatulence, tenesmus,meteorism, an increased frequency of stools, a feeling of fullness andupper abdominal cramps.

In the present context, a reduction of GI related side effects isintended to denote a decrease in severity and/or incidence among a giventreated patient population, comparing the GI side effects observed afteradministration of the formulation according to the invention to the GIside effects observed after administration of Fumaderm®. A reduction inGI related side effects according to this definition could thus beconstrued as a substantial reduction in incidence of any of the GI sideeffect listed above, such as at least a 10% reduction in incidence ormore preferably at least 20% reduction in incidence or even morepreferable a more than 30% reduction in incidence. A reduction in GIrelated side effect can also be expressed as a substantial reduction inseverity in any of the GI side effects listed above, such as a reductionin severity and/or frequency of diarrhea, stomach ache, stomach pain,abdominal pain, abdominal cramps, nausea, flatulence, tenesmus,meteorism, increased frequency of stools, a feeling of fullness or upperabdominal cramps. The reduction of GI related side effects, as describedabove, can be monitored in a clinical trial setting, either comparingthe administration of the formulation according to the invention head onwith Fumaderm® or with placebo. In case of a placebo controlled trial,the incidence of GI related side effects in the patients receiving theformulation according to the invention compared to the placebo group,can be compared to historical trials comparing Fumaderm® to placebo (seee.g. Altmeyer et al, J. Am. Acad. Dermatol. 1994; full reference:Altmeyer P J et al, Antipsoriatic effect of fumaric acid derivatives.Results of a multicenter double-blind study in 100 patients. J. Am.Acad. Dermatol. 1994; 30:977-81).

In a further aspect, the formulation according to the invention—uponoral administration and in comparison to that obtained after oraladministration of Fumaderm® tablets in an equivalent dosage—reduce (GI)side-effects (frequency and/or severity).

In one embodiment, such a clinical trial can be carried out as describedbelow under “Clinical trial in patients”. In another embodiment, such aclinical trial can be carried out as described below under “Clinicaltrial in healthy volunteers”.

Clinical trial in patients: Typically, patients suffering from psoriasisare included in such a study, and typically more than 10% of the bodysurface area will be affected by psoriasis (severe psoriasis). However,patients in whom between 2 and 10 percent of the body surface area isaffected can also be included (moderate psoriasis). Patients can also beselected based on the psoriasis area severity index (PASI) score.Typically, patients within a certain range of PASI scores are included,such as between 10 and 40, or such as between 12 and 30, or such asbetween 15 and 25. In another embodiment, patients with a certainminimum PASI score are included, such as a PASI score of at least 8,such as at least 10, such as at least 12, such as at least 15. Patientswith any type of psoriasis may be included (chronic plaque type,exanthematic guttate type, pustular type, psoriatic erythroderma orpalmoplantar type), but in some cases only patients with the chronicplaque type are included. About 15 to 20 patients in each treatmentgroup (formulation according to the invention, Fumaderm® or placebo) aresufficient in most cases, but more preferably about 30 to 50 patientsare included in each arm of the study. Total study duration can be asshort as one day to one week, but more preferably the study will run for8 weeks to 12 weeks or up to 16 weeks or longer. The side effects cane.g. be assessed as the total number of times a certain side effect wasreported in each group (irrespective of how many patients haveexperienced the side effect), or the side effects can be assessed as thenumber of patients that have experienced a certain side effect a certainnumber of times, such as at least once or at least twice or at leastthree times during the duration of the study. Furthermore, the severityof a side effect can be monitored, or a certain severity of a sideeffect can be required for it to qualify as a side effect in the study.A convenient way of assessing the severity of a side effect is via avisual analogue (VAS) scale.

Clinical trial in healthy volunteers: This study will typically be asingle center study, following an open-label, randomized, crossoverdesign to investigate the plasma concentrations, pharmacokinetics,safety and tolerability of pharmaceutical formulations according to theinvention, possibly using the marketed formulation Fumaderm® asreference. The trial may be carried out as disclosed in detail inexample 25 below.

In a further aspect, the formulation according to the invention—uponoral administration and in comparison to that obtained after oraladministration of Fumaderm® tablets in an equivalent dosage—reduceflushing (frequency and/or severity).

In the present context the term “flushing” describes episodic attacks ofredness of the skin together with a sensation of warmth or burning ofthe face and/or neck, and less frequently the upper trunk and abdomen orthe whole body. It is the transient nature of the attacks thatdistinguishes flushing from the persistent erythema of photosensitivityor acute contact reactions. Repeated flushing over a prolonged period oftime can lead to telangiectasia and occasionally to classical rosacea ofthe face (Greaves M W. Flushing and flushing syndromes, rosacea andperioral dermatitis. In: Champion R H, et al, eds. Rook/Wilkinson/Eblingtextbook of dermatology, 6th ed., vol. 3. Oxford, UK: BlackwellScientific, 1998: 2099-2104).

In the present context, a reduction of flushing is intended to denote adecrease in severity and/or incidence/frequency among a given treatedpatient population of flushing observed after administration of theformulation according to the invention compared with flushing observedafter administration of Fumaderm® and can be measured e.g as describedby O'toole et al. Cancer 2000, 88(4): p. 770-776. A reduction influshing according to this definition could thus be construed as areduction in incidence and/or severity of flushing. In one aspect of theinvention, the incidence of flushing is reduced by at least about aquarter, in another aspect of the invention the incidence is reduced byat least about a third, in another aspect of the invention the incidenceis reduced by at least about half, and in a further aspect of theinvention, the flushing incidence is reduced by about two thirds ormore. Likewise, the severity is in one aspect of the invention reducedby at least about a quarter, in another aspect of the invention by atleast about a third, in another aspect of the invention by at leasthalf, and in a further aspect of the invention by at least about twothirds. A one hundred percent reduction in flushing incidence andseverity is most preferable, but is not required. The reduction offlushing, as described above, can be monitored in a clinical trialsetting, e.g. comparing the administration of the compound according tothe invention with e.g. administration of Fumaderm®. In case of aFumaderm® controlled trial, the incidence and severity, defined as mild,moderate or severe, of flushing in the patients receiving the compoundaccording to the invention compared to the Fumaderm® group, can becompared.

In one aspect, the severity of flushing is determined as the bodysurface area involved.

In one embodiment, such a clinical trial can be carried out as describedabove under “Clinical trial in patients”. In another embodiment, such aclinical trial can be carried out as described above under “Clinicaltrial in healthy volunteers”.

In a further aspect, the formulation according to the invention—uponoral administration and in comparison to that obtained after oraladministration of Fumaderm® tablets in an equivalent dosage—reduceredness (frequency and/or severity).

In the present context the term “redness” describes episodic attacks ofredness of the skin. In one aspect, the redness occurs in the face,neck, and less frequently the upper trunk and abdomen.

In the present context, a reduction of redness is intended to denote adecrease in severity and/or incidence/frequency among a given treatedpatient population of redness observed after administration of theformulation according to the invention compared with redness observedafter administration of Fumaderm® and can e.g. be assessed by aclinician or nurse. A reduction in redness according to this definitioncould thus be construed as a reduction in incidence and/or severity ofredness. In one aspect of the invention, the incidence of redness isreduced by at least about a quarter, in another aspect of the inventionthe incidence is reduced by at least about a third, in another aspect ofthe invention the incidence is reduced by at least about half, and in afurther aspect of the invention, the redness incidence is reduced byabout two thirds or more. Likewise, the severity is in one aspect of theinvention reduced by at least about a quarter, in another aspect of theinvention by at least about a third, in another aspect of the inventionby at least half, and in a further aspect of the invention by at leastabout two thirds. A one hundred percent reduction in redness incidenceand severity is most preferable, but is not required. The reduction ofredness, as described above, can be monitored in a clinical trialsetting, e.g. comparing the administration of the compound according tothe invention with e.g. administration of Fumaderm®. In case of aFumaderm® controlled trial, the incidence and severity, defined as mild,moderate or severe, of redness in the patients receiving the compoundaccording to the invention compared to the Fumaderm® group, can becompared.

In one aspect, the severity of redness is determined as the body surfacearea involved.

In one embodiment, such a clinical trial can be carried out as describedabove under “Clinical trial in patients”. In another embodiment, such aclinical trial can be carried out as described above under “Clinicaltrial in healthy volunteers”.

In one embodiment, the relative bioavailability of the formulation ofthe invention compared to Fumaderm® is at least about 75%, such as atleast about 80%, such as at least about 85%, such as at least about 90%,such as at least about 95%, such as about 100%.

In one embodiment, the relative bioavailability of the formulation ofthe invention compared to Fumaderm® is at least about 100%, such as atleast about 110%, such as at least about 120%, such as at least about125%, such as at least about 130%.

In one embodiment, the relative bioavailability of the formulation ofthe invention compared to Fumaderm® is at the most about 130%, such asat the most about 125%, such as at the most about 120%, such as at themost about 110%, such as at the most about 100%.

In the present context the term “erosion matrix” refers to a matrixwherein the release of the API does not depend upon intrinsic diffusionprocesses but rather is the result of the rate of the matrix erosion. Bystripping off the erodible matrix layers in a well controlled manner,predetermined amounts of the API will be obtained, with the release ofAPI being dependent on the rate of swelling and dissolution or erosionof the matrix and on the rate of dissolution, solubility and rate ofdiffusion of the API.

In an aspect the present invention relates to a pharmaceuticalformulation comprising an erosion matrix which comprises:

-   -   i) 10% to 80%, such as 20% to 70%, such as 20% to 60%, such as        30% to 60%, such as 35% to 60%, such as 35% to 55%, such as 40%        to 55%, such as 44% to 55%, such as 40% to 50%, such as 42% to        48% by weight of one or more fumaric acid esters selected from        di-(C₁-C₅)alkylesters of fumaric acid and        mono-(C₁-C₅)alkylesters of fumaric acid, or a pharmaceutically        acceptable salt thereof, as an active substance; and    -   ii) 1% to 50% by weight of one or more rate-controlling agents;

wherein erosion of said erosion matrix permits controlled or sustainedrelease of said active substance

In an aspect the present invention relates to a pharmaceuticalformulation comprising an erosion matrix which comprises:

-   -   i) 30% to 60%, such as 35% to 60%, such as 35% to 55%, such as        40% to 55%, such as 40% to 50%, such as 44% to 55%, such as 42%        to 48% by weight of one or more fumaric acid esters selected        from di-(C₁-C₅)alkylesters of fumaric acid and        mono-(C₁-C₅)alkylesters of fumaric acid, or a pharmaceutically        acceptable salt thereof, as an active substance; and    -   ii) 3% to 40% by weight of one or more rate-controlling agents;

wherein erosion of said erosion matrix permits controlled or sustainedrelease of said active substance.

In some embodiments of the invention, it has been found that it ispossible to obtain sustained release with a relatively low amount ofrate-controlling agent while still obtaining sufficient drug exposure inthe narrow window of absorption available in the small intestine, andthereby providing favourable pharmaco-kinetic properties, such asadequate relative bioavailability c.f. e.g. the prior art Fumaderm®formulation.

In some further embodiments, it has been found that it is possible toobtain enteric coated sustained release formulations according to theinvention while still obtaining sufficient drug exposure in the narrowwindow of absorption available in the small intestine, and therebyproviding favourable pharmaco-kinetic properties, such as adequaterelative bioavailability c.f. e.g. the prior art Fumaderm® formulation.

In an aspect of the invention, the rate-controlling agent is awater-soluble polymer.

As used herein, the term “water-soluble polymer” means a conventionalpolymer for pharmaceutical use, having a solubility of more than 10mg/ml in water. Suitable water-soluble polymers includes, but are notlimited too, for example, hydroxypropylmethyl cellulose, hydroxypropylcellulose, methyl cellulose and carboxymethyl cellulose. In one aspect,the water-soluble polymer is hydroxypropyl cellulose.

As used herein, the term “water-insoluble polymer” means a conventionalpolymer for pharmaceutical use, having a solubility of not more than 10mg/ml in water.

In a further aspect of the invention, the erosion matrix containsessentially no water-insoluble polymer. In yet a further aspect, theerosion matrix contains no water-insoluble polymer.

In the present context the term “essentially no” refers to a level ofless than about 1%, such as less than about 0.5%, such as less thanabout 0.3%, such as about 0.0%.

In an aspect of the invention, the rate-controlling agent is awater-soluble polymer and the erosion matrix contains essentially nowater-insoluble polymer.

In an aspect of the invention, the rate-controlling agent is awater-soluble polymer and the erosion matrix contains no water-insolublepolymer.

In an embodiment of the invention, the rate-controlling agent is acellulose polymer or a cellulose derivative or a mixture thereof. Asnon-limiting examples of a cellulose polymer or a cellulose derivativeor a mixture thereof may be mentioned hydroxypropyl cellulose,hydroxypropyl methyl cellulose (HPMC), methyl cellulose, carboxymethylcellulose and mixtures thereof.

In an embodiment of the invention the rate-controlling agent ishydroxypropyl cellulose. Many different grades of hydroxypropylcellulose exist depending on e.g. the molecular weight thereof, thedegree of etherification, viscosity etc. Non-limiting exemplaryembodiments of commercially available hydroxypropyl celluloses areobtainable from e.g. Aqualon or Nippon Soda under the trade namesKlucel® HPC-L, HPC-SL, HPC-SSL, HPC-M, HPC-H etc. In an embodiment ofthe invention, the rate-controlling agent is hydroxypropyl cellulosehaving a viscosity (mPa·s) of 3.0-5.9 as measured in an aqueous solutioncontaining 2% by weight of dry HPC at 20° C. In an embodiment of theinvention, the rate-controlling agent is HPC-SL.

In an embodiment of the invention the rate-controlling agent is presentin an amount of 1-40% by weight, such as about 3-35% by weight, such asabout 4-15% by weight, such as about 4-10% by weight, such as about3-15% by weight, such as about 3-10% by weight, such as about 3-6% byweight, such as about 3-5.5% by weight, such as about 4-6% by weight.

In an embodiment of the invention the rate-controlling agent is presentin an amount of 1-40% by weight, such as 3-35% by weight, such as 4-15%by weight, such as 4-10% by weight, such as 3-15% by weight, such as3-10% by weight, such as 3-6% by weight, such as 3-5.5% by weight, suchas 4-6% by weight.

In another embodiment of the invention, the rate-controlling agent ispresent in an amount of 15-40% by weight, such as about 15-25% byweight.

In another embodiment of the invention, the rate-controlling agent ispresent in an amount of about 25-40% by weight, such as about 35-40% byweight.

In another embodiment of the invention, the rate-controlling agent ispresent in an amount of about 0-5% by weight, such as about 0-3% byweight, such as in substantial absence of any rate-controlling agent.

In an aspect, the present invention relates to a pharmaceuticalformulation comprising an erosion matrix which comprises:

-   -   i) 10% to 80%, such as 20% to 70%, such as 20% to 60%, such as        30% to 60%, such as 35% to 60%, such as 35% to 55%, such as 40%        to 55%, such as 40% to 50%, such as 44% to 55%, such as 42% to        48%, by weight of one or more fumaric acid esters selected from        di-(C₁-C₅)alkylesters of fumaric acid and        mono-(C₁-C₅)alkylesters of fumaric acid, or a pharmaceutically        acceptable salt thereof, as an active substance; and    -   ii) 0% to 40%, such as 0% to 20%, such as 0% to 10%, such as 0%        to 5%, such as 0% to 1%, by weight of one or more        rate-controlling agents;

wherein erosion of said erosion matrix permits controlled release ofsaid active substance.

The amount, if any, of rate-controlling agent varies in accordance withthe specific rate-controlling agent used, the release profile aimed at,the level and nature of any excipients and additives present in the coretablet, etc.

In an embodiment of the invention the formulation further comprises abinder. Non-limiting examples thereof include water-soluble sugars andsugar alcohols, such as lactose, saccharose, glucose, sorbitol, mannitoletc. In an embodiment thereof, said binder is lactose.

Lactose is commercially available in a number of different gradesdepending i.a. on the manufacturing method used resulting in a range ofparticle sizes, particle size distributions etc. Examples of lactoseinclude, but are not limited to anhydrous lactose, lactose made fromalpha-lactose-monohydrate, agglomerated lactose, granulated lactose,crystalline lactose, crystalline, sieved lactose, sieved lactose (e.g.PrismaLac®, such as PrismaLac® 40), crystalline, abrasive lactose (e.g.GranuLac®, such as GranuLac® 70, GranuLac® 140, GranuLac® 200, GranuLac®230 and GranuLac® 400), improved lactose, agglomerated lactose (e.g.Tablettose®, such as Tablettose® 70, Tablettose® 80 and Tablettose®100), improved lactose, spraydried lactose (FlowLac®, such as FlowLac®90 and FlowLac® 100). Lactose is available from e.g. Meggle Pharma underthe trade names PrismaLac®, Capsulac®, such as Capsulac®60, SacheLac®,SpheroLac®, Inhalac® GranuLac®, such as GranuLac® 70, GranuLac® 140,GranuLac® 200, GranuLac® 230 and GranuLac® 400, SorboLac®, Tablettose®,such as Tablettose® 70, Tablettose® 80 and Tablettose® 100, FlowLac®,such as FlowLac® 90 and FlowLac® 100.

In one aspect, the lactose is agglomerated lactose. In another aspect,the lactose is spraydried lactose. In another aspect, the lactose isabrasive lactose.

In an embodiment of the invention, the formulation according to theinvention comprises:

-   -   i) 40% to 60% by weight of one or more fumaric acid esters        selected from di-(C₁-C₅)alkylesters of fumaric acid and        mono-(C₁-C₅)alkylesters of fumaric acid, or a pharmaceutically        acceptable salt thereof, as an active substance;    -   ii) 4-6% by weight of a rate-controlling agent;    -   iii) 35-55% by weight of a binder.

In an embodiment of the invention, the formulation according to theinvention comprises:

-   -   i) 40% to 60% by weight of one or more fumaric acid esters        selected from di-(C₁-C₅)alkylesters of fumaric acid and        mono-(C₁-C₅)alkylesters of fumaric acid, or a pharmaceutically        acceptable salt thereof, as an active substance;    -   ii) 15-50% by weight of a rate-controlling agent;    -   iii) 5-30% by weight of a binder.

In an embodiment of the invention, the formulation according to theinvention comprises:

-   -   i) 30% to 60% by weight of one or more fumaric acid esters        selected from di-(C₁-C₅)alkylesters of fumaric acid and        mono-(C₁-C₅)alkylesters of fumaric acid, or a pharmaceutically        acceptable salt thereof, as an active substance;    -   ii) 3-6% by weight of rate-controlling agent;    -   iii) 35-65% by weight of binder.

In an embodiment of the invention, the formulation according to theinvention comprises:

-   -   i) 35% to 55% by weight of one or more fumaric acid esters        selected from di-(C₁-C₅)alkylesters of fumaric acid and        mono-(C₁-C₅)alkylesters of fumaric acid, or a pharmaceutically        acceptable salt thereof, as an active substance;    -   ii) 3-6% by weight of rate-controlling agent;    -   iii) 40-60% by weight of binder.

In an embodiment of the invention, the formulation according to theinvention comprises:

-   -   i) 40% to 50% by weight of one or more fumaric acid esters        selected from di-(C₁-C₅)alkylesters of fumaric acid and        mono-(C₁-C₅)alkylesters of fumaric acid, or a pharmaceutically        acceptable salt thereof, as an active substance;    -   ii) 3-6% by weight of rate-controlling agent;    -   iii) 45-55% by weight of binder.

In an embodiment of the invention, the formulation according to theinvention comprises:

-   -   i) 42% to 48% by weight of one or more fumaric acid esters        selected from di-(C₁-C₅)alkylesters of fumaric acid and        mono-(C₁-C₅)alkylesters of fumaric acid, or a pharmaceutically        acceptable salt thereof, as an active substance;    -   ii) 3-5.5% by weight of rate-controlling agent;    -   iii) 45-52% by weight of binder.

In an embodiment of the invention, the formulation according to theinvention comprises:

-   -   i) 30% to 60% by weight of one or more fumaric acid esters        selected from di-(C₁-C₅)alkylesters of fumaric acid and        mono-(C₁-C₅)alkylesters of fumaric acid, or a pharmaceutically        acceptable salt thereof, as an active substance;    -   ii) 3-6% by weight of rate-controlling agent;    -   iii) 35-65% by weight of binder;    -   iv) 0.15-0.7% by weight of lubricant;    -   and optionally 0.05-0.25% by weight of flow control agents.

In an embodiment of the invention, the formulation according to theinvention comprises:

-   -   i) 35% to 55% by weight of one or more fumaric acid esters        selected from di-(C₁-C₅)alkylesters of fumaric acid and        mono-(C₁-C₅)alkylesters of fumaric acid, or a pharmaceutically        acceptable salt thereof, as an active substance;    -   ii) 3-6% by weight of rate-controlling agent;    -   iii) 40-60% by weight of binder;    -   iv) 0.15-0.7% by weight of lubricant;    -   and optionally 0.05-0.25% by weight of flow control agents.

In an embodiment of the invention, the formulation according to theinvention comprises:

-   -   i) 40% to 50% by weight of one or more fumaric acid esters        selected from di-(C₁-C₅)alkylesters of fumaric acid and        mono-(C₁-C₅)alkylesters of fumaric acid, or a pharmaceutically        acceptable salt thereof, as an active substance;    -   ii) 3-6% by weight of rate-controlling agent;    -   iii) 45-55% by weight of binder;    -   iv) 0.15-0.7% by weight of lubricant;    -   and optionally 0.05-0.25% by weight of flow control agents.

In an embodiment of the invention, the formulation according to theinvention comprises:

-   -   i) 42% to 48% by weight of one or more fumaric acid esters        selected from di-(C₁-C₅)alkylesters of fumaric acid and        mono-(C₁-C₅)alkylesters of fumaric acid, or a pharmaceutically        acceptable salt thereof, as an active substance;    -   ii) 3-5.5% by weight of rate-controlling agent;    -   iii) 45-52% by weight of binder;    -   iv) 0.2-0.5% by weight of lubricant;    -   and optionally 0.05-0.2% by weight of flow control agents.

In an embodiment of the invention, the formulation according to theinvention comprises:

-   -   i) 30% to 60% by weight of dimethyl fumarate;    -   ii) 3-6% by weight of HPC;    -   iii) 35-65% by weight of lactose.

In an embodiment of the invention, the formulation according to theinvention comprises:

-   -   i) 35% to 55% by weight of dimethyl fumarate;    -   ii) 3-6% by weight of HPC;    -   iii) 40-60% by weight of lactose.

In an embodiment of the invention, the formulation according to theinvention comprises:

-   -   i) 40% to 50% by weight of dimethyl fumarate;    -   ii) 3-6% by weight of HPC;    -   iii) 45-55% by weight of lactose.

In an embodiment of the invention, the formulation according to theinvention comprises:

-   -   i) 42% to 48% by weight of dimethyl fumarate;    -   ii) 3-5.5% by weight of HPC;    -   iii) 45-52% by weight of lactose.

In an embodiment of the invention, the formulation according to theinvention comprises:

-   -   i) 30% to 60% by weight of dimethyl fumarate;    -   ii) 3-6% by weight of HPC;    -   iii) 35-65% by weight of lactose;    -   iv) 0.15-0.7% by weight of magnesium stearate;    -   and optionally 0.05-0.25% by weight of silicon dioxide.

In an embodiment of the invention, the formulation according to theinvention comprises:

-   -   i) 35% to 55% by weight of dimethyl fumarate;    -   ii) 3-6% by weight of HPC;    -   iii) 40-60% by weight of lactose;    -   iv) 0.15-0.7% by weight of magnesium stearate;    -   and optionally 0.05-0.25% by weight of silicon dioxide.

In an embodiment of the invention, the formulation according to theinvention comprises:

-   -   i) 40% to 50% by weight of dimethyl fumarate;    -   ii) 3-6% by weight of HPC;    -   iii) 45-55% by weight of lactose;    -   iv) 0.15-0.7% by weight of magnesium stearate;    -   and optionally 0.05-0.25% by weight of silicon dioxide.

In an embodiment of the invention, the formulation according to theinvention comprises:

-   -   i) 42% to 48% by weight of dimethyl fumarate;    -   ii) 3-5.5% by weight of HPC;    -   iii) 45-52% by weight of lactose;    -   iv) 0.2-0.5% by weight of magnesium stearate;    -   and optionally 0.05-0.2% by weight of silicon dioxide.

In an embodiment of the invention, the formulation according to theinvention comprises:

-   -   A) A tablet core consisting of:    -   i) 30% to 60% by weight of dimethyl fumarate as an active        substance having a particle size distribution such that 0-5% of        the particles have a particle size >500 μm and 45-53% of the        particles have a particle size >250 μm, and 7-15% of the        particles have a particle size <100 μm;    -   ii) 3-6% by weight of HPC;    -   iii) 35-65% by weight of lactose;    -   iv) 0.15-0.7% by weight of magnesium stearate and 0.05-0.25% by        weight of silicon dioxide; and    -   B) an enteric coating in an amount of about 1.5-3.5% by weight        of the core.

In an embodiment of the invention, the formulation according to theinvention comprises:

-   -   A) A tablet core consisting of:    -   i) 35% to 55% by weight of dimethyl fumarate as an active        substance having a particle size distribution such that 0-5% of        the particles have a particle size >500 μm and 45-53% of the        particles have a particle size >250 μm, and 7-15% of the        particles have a particle size <100 μm;    -   ii) 3-6% by weight of HPC;    -   iii) 40-60% by weight of lactose;    -   iv) 0.15-0.7% by weight of magnesium stearate and 0.05-0.25% by        weight of silicon dioxide; and    -   B) an enteric coating in an amount of about 1.5-3.5% by weight        of the core.

In an embodiment of the invention, the formulation according to theinvention comprises:

-   -   A) A tablet core consisting of:    -   i) 40% to 50% by weight of dimethyl fumarate as an active        substance having a particle size distribution such that 0-5% of        the particles have a particle size >500 μm and 45-53% of the        particles have a particle size >250 μm, and 7-15% of the        particles have a particle size <100 μm;    -   ii) 3-6% by weight of HPC;    -   iii) 45-55% by weight of lactose;    -   iv) 0.15-0.7% by weight of magnesium stearate and 0.05-0.25% by        weight of silicon dioxide; and    -   B) an enteric coating in an amount of about 1.5-3.5% by weight        of the core.

In an embodiment of the invention, the formulation according to theinvention comprises:

-   -   A) A tablet core consisting of:    -   i) 42% to 48% by weight of dimethyl fumarate as an active        substance having a particle size distribution such that 0-5% of        the particles have a particle size >500 μm and 45-53% of the        particles have a particle size >250 μm, and 7-15% of the        particles have a particle size <100 μm;    -   ii) 3-5.5% by weight of HPC;    -   iii) 45-52% by weight of lactose;    -   iv) 0.2-0.5% by weight of magnesium stearate and 0.05-0.2% by        weight of silicon dioxide; and    -   B) an enteric coating in an amount of about 1.5-3.5% by weight        of the core.

In an embodiment of the invention, the formulation according to theinvention comprises:

-   -   A) A tablet core consisting of:    -   i) 30% to 60% by weight of dimethyl fumarate as an active        substance having a particle size distribution such that 0-7% of        the particles have a particle size >500 μm and 42-59% of the        particles have a particle size >250 μm, and 3-12% of the        particles have a particle size <100 μm;    -   ii) 3-6% by weight of HPC;    -   iii) 35-65% by weight of lactose;    -   iv) 0.15-0.7% by weight of magnesium stearate and 0.05-0.25% by        weight of silicon dioxide; and    -   B) an enteric coating in an amount of about 1.5-3.5% by weight        of the core.

In an embodiment of the invention, the formulation according to theinvention comprises:

-   -   A) A tablet core consisting of:    -   i) 35% to 55% by weight of dimethyl fumarate as an active        substance having a particle size distribution such that 0-7% of        the particles have a particle size >500 μm and 42-59% of the        particles have a particle size >250 μm, and 3-12% of the        particles have a particle size <100 μm;    -   ii) 3-6% by weight of HPC;    -   iii) 40-60% by weight of lactose;    -   iv) 0.15-0.7% by weight of magnesium stearate and 0.05-0.25% by        weight of silicon dioxide; and    -   B) an enteric coating in an amount of about 1.5-3.5% by weight        of the core.

In an embodiment of the invention, the formulation according to theinvention comprises:

-   -   A) A tablet core consisting of:    -   i) 40% to 50% by weight of dimethyl fumarate as an active        substance having a particle size distribution such that 0-7% of        the particles have a particle size >500 μm and 42-59% of the        particles have a particle size >250 μm, and 3-12% of the        particles have a particle size <100 μm;    -   ii) 3-6% by weight of HPC;    -   iii) 45-55% by weight of lactose;    -   iv) 0.15-0.7% by weight of magnesium stearate and 0.05-0.25% by        weight of silicon dioxide; and    -   B) an enteric coating in an amount of about 1.5-3.5% by weight        of the core.

In an embodiment of the invention, the formulation according to theinvention comprises:

-   -   A) A tablet core consisting of:    -   i) 42% to 48% by weight of dimethyl fumarate as an active        substance having a particle size distribution such that 0-7% of        the particles have a particle size >500 μm and 42-59% of the        particles have a particle size >250 μm, and 3-12% of the        particles have a particle size <100 μm;    -   ii) 3-5.5% by weight of HPC;    -   iii) 45-52% by weight of lactose;    -   iv) 0.2-0.5% by weight of magnesium stearate and 0.05-0.2% by        weight of silicon dioxide; and    -   B) an enteric coating in an amount of about 1.5-3.5% by weight        of the core.

In an embodiment of the invention, the formulation according to theinvention comprises:

-   -   A) A tablet core consisting of:    -   i) 30% to 60% by weight of dimethyl fumarate as an active        substance having a particle size distribution such that 0-10% of        the particles have a particle size >500 μm and 40-65% of the        particles have a particle size >250 μm, and 2-10% of the        particles have a particle size <100 μm;    -   ii) 3-6% by weight of HPC;    -   iii) 35-65% by weight of lactose;    -   iv) 0.15-0.7% by weight of magnesium stearate and 0.05-0.25% by        weight of silicon dioxide; and    -   B) an enteric coating in an amount of about 1.5-3.5% by weight        of the core.

In an embodiment of the invention, the formulation according to theinvention comprises:

-   -   A) A tablet core consisting of:    -   i) 35% to 55% by weight of dimethyl fumarate as an active        substance having a particle size distribution such that 0-10% of        the particles have a particle size >500 μm and 40-65% of the        particles have a particle size >250 μm, and 2-10% of the        particles have a particle size <100 μm;    -   ii) 3-6% by weight of HPC;    -   iii) 40-60% by weight of lactose;    -   iv) 0.15-0.7% by weight of magnesium stearate and 0.05-0.25% by        weight of silicon dioxide; and    -   B) an enteric coating in an amount of about 1.5-3.5% by weight        of the core.

In an embodiment of the invention, the formulation according to theinvention comprises:

-   -   A) A tablet core consisting of:    -   i) 40% to 50% by weight of dimethyl fumarate as an active        substance having a particle size distribution such that 0-10% of        the particles have a particle size >500 μm and 40-65% of the        particles have a particle size >250 μm, and 2-10% of the        particles have a particle size <100 μm;    -   ii) 3-6% by weight of HPC;    -   iii) 45-55% by weight of lactose;    -   iv) 0.15-0.7% by weight of magnesium stearate and 0.05-0.25% by        weight of silicon dioxide; and    -   B) an enteric coating in an amount of about 1.5-3.5% by weight        of the core.

In an embodiment of the invention, the formulation according to theinvention comprises:

-   -   A) A tablet core consisting of:    -   i) 42% to 48% by weight of dimethyl fumarate as an active        substance having a particle size distribution such that 0-10% of        the particles have a particle size >500 μm and 40-65% of the        particles have a particle size >250 μm, and 2-10% of the        particles have a particle size <100 μm;    -   ii) 3-5.5% by weight of HPC;    -   iii) 45-52% by weight of lactose;    -   iv) 0.2-0.5% by weight of magnesium stearate and 0.05-0.2% by        weight of silicon dioxide; and    -   B) an enteric coating in an amount of about 1.5-3.5% by weight        of the core.

In an embodiment the formulation according to the invention furthercomprises one or more lubricants.

In an embodiment the formulation according to the invention furthercomprises one or more flow control agents.

In an embodiment the formulation according to the invention furthercomprises one or more lubricants and one or more flow control agents.

In an embodiment the formulation according to the invention furthercomprises pharmaceutically acceptable excipients and additives selectedfrom the group comprising lubricants, glidants, disintegrants, flowcontrol agents, solubilizers, pH control agents, surfactants andemulsifiers.

In an embodiment, the formulation according to the invention ismanufactured without the use of a disintegrant.

Some of the formulations according to the invention show bi-phasic invitro dissolution profiles, wherein the release of the API such asdimethyl fumarate is slower while in the acidic environment of the firsttwo hours of a USP dissolution apparatus, and faster once thedissolution medium is changed to pH 6.8, even though the solubility ofthe API may be the same in acid and alkaline environment. For drugswhere a relatively low exposure to the stomach is desired, but at thesame time requiring release/absorption in the small intestine it willthereby be possible to limit the exposure of the API to the stomachwhile optimising the exposure of the API to the small intestine. In anembodiment the in vitro dissolution profile of the formulation isbi-phasic i.e. the release of the API is slower while in the acidicenvironment of the first two hours of a USP dissolution apparatus, andfaster once the dissolution medium is changed to pH 6.8.

The in vitro dissolution rate describes how the amount released of theAPI contained in a formulation according to the invention—when subjectedto an in vitro dissolution test—changes over time. A higher/faster invitro dissolution rate means that a larger amount of the API is releasedover a certain period of time, and a lower/slower in vitro dissolutionrate means that a smaller amount of the API is released over the sameperiod of time—when subjected to the same in vitro dissolution testingconditions.

In an embodiment of the invention, the in vitro dissolution test usedfor determining the in vitro dissolution rate employs 0.1 N hydrochloricacid as dissolution medium during the first 2 hours of the test and then0.05 M phosphate buffer pH 6.8 as dissolution medium.

In an embodiment of the invention, the in vitro dissolution rate of theAPI contained in a non-enteric coated formulation according to theinvention—when subjected to an in vitro dissolution test employing 0.1 Nhydrochloric acid as dissolution medium during the first 2 hours of thetest and then 0.05 M phosphate buffer pH 6.8 as dissolution medium—ishigher in the buffer (pH 6.8) phase c.f. the acid phase (0.1 Nhydrochloric acid as dissolution medium) of the in vitro dissolutiontest, such as at least 10% higher, such as at least 20% higher, such asat least 30% higher, such as at least 40% higher, such as at least 50%higher, such as at least 60% higher, such as at least 70% higher, suchas at least 80% higher, such as at least 90% higher, such as at least100% higher, such as at least 125% higher, such as at least 150% higher,such as at least 200% higher, such as at least 250% higher, such as atleast 300% higher, such as at least 350% higher, such as at least 400%higher in the buffer (pH 6.8) phase c.f. the acid phase (0.1 Nhydrochloric acid as dissolution medium) of the in vitro dissolutiontest. In an embodiment the comparison is made between the in vitrodissolution rate during the first hour of the test (between time=0 andtime=1 hour) and the in vitro dissolution rate in the third hour(between time=2 hours and time=3 hours) of the test. In anotherembodiment the comparison is made between the in vitro dissolution rateduring the first two hours of the test (between time=0 and time=2 hours)and the in vitro dissolution rate in the third hour (between time=2hours and time=3 hours) of the test. In another embodiment thecomparison is made between the in vitro dissolution rate during thefirst two hours of the test (between time=0 and time=2 hours) and the invitro dissolution rate in the subsequent two hours (between time=2 hoursand time=4 hours) of the test. In another embodiment the comparison ismade between the in vitro dissolution rate during the first hour of thetest (between time=0 and time=1 hour) and the in vitro dissolution ratebetween time=2 hours and time=2.5 hours of the test.

In an embodiment the formulation according to the invention furthercomprises one or more coatings. In an embodiment of the invention saidone or more coatings are added in order to improve stability andswallowing characteristics of the tablets or to delay release of theAPI. In an embodiment thereof said coatings are film coatings and/orenteric coatings. The film coating may improve swallowingcharacteristics as well as stability and can also mitigate the risk ofsublimation of the active pharmaceutical ingredient. Furthermore, thefilm coating may improve the safety aspect of handling the tablets. Afilm coat with an overlying enteric coat, or an enteric coat by itselfmay have similar benefits to the ones listed above for film coating.However, in addition, the active pharmaceutical ingredient may not bereleased in the acidic environment of the gastric ventricle, potentiallyprotecting the gastric mucosa from irritation, if the API has anirritant potential for the gastric mucosa.

In an embodiment of the invention said coating is an enteric coating.

Enteric coating materials may be selected from any of a number ofcommercially available coating materials. Non-limiting examples thereofinclude Eudragit® E, L, S, L30D55, Kollicoat® 30D, Cellulose AcetatePhthalate, Polyvinyl Acetate Phthalate, and Hypromellose Phthalate.

In an embodiment of the invention said enteric coating is applied at alevel of about 1.0-5.0% by weight of the core.

In an embodiment of the invention said enteric coating is applied at alevel of about 1.0-4.5% by weight of the core, such as 1.5-4.0% byweight of the core, such as about 1.5-3.5% by weight of the core, suchas about 2.0-3.5% by weight of the core, such as about 2-3% by weight ofthe core.

In an embodiment of the invention said enteric coating is applied at alevel of about 1.5-3.5% by weight of the core.

Enteric coating is a well established approach to prevent or minimisedrug release in the stomach and allow release in the small intestine.Such enteric polymer coatings work on the principle of pH dependentsolubility: insoluble in the low pH conditions of the stomach butsoluble in the near neutral pH environment of the proximal smallintestine having a pH in the range 5-6.

For drugs requiring absorption in the small intestine this leaves openonly a narrow window of release, such as about 5 hours, such as about 4hours, such as about 3 hours, such as about 22 hours, such as about 2hours between solubilisation of the enteric coating and release of theAPI from the formulation. In some embodiments of the invention, it hasbeen found that rapid solubilisation of the enteric coating is possibleby the application of a relatively thin coat while surprisingly stillobtaining the required protection against the acid environment of thestomach as e.g. shown—when subjected to an in vitro dissolution testemploying 0.1 N hydrochloric acid as dissolution medium during 2hours—by less than 10%, such as less than 5%, such as less than 2%, suchas about 0% release of the fumaric ester contained in the formulation.

In an embodiment of the invention the in vivo release of the fumaricacid ester displays an earlier onset of release than the prior artformulation Fumaderm®, such as at least 20 minutes, at least 30 minutes,at least 40 minutes, at least 50 minutes, at least 60 minutes, at least70 minutes, at least 80 minutes, at least 90 minutes, at least 100minutes, at least 110 minutes, or at least 120 minutes earlier thanFumaderm® under fasting conditions.

In an embodiment of the invention, the formulation according to theinvention comprises an enteric coating and the in vivo release of thefumaric acid ester displays an earlier onset of release than the priorart formulation Fumaderm®, such as at least 20 minutes, at least 30minutes, at least 40 minutes, at least 50 minutes, at least 60 minutes,at least 70 minutes, at least 80 minutes, at least 90 minutes, at least100 minutes, at least 110 minutes, or at least 120 minutes earlier thanFumaderm® under fasting conditions.

In an embodiment of the invention the in vivo release of the fumaricacid ester displays a lag time of 15 minutes to 2 hours under fastingconditions, such as a lag time of at the most 120 minutes, at the most110 minutes, at the most 100 minutes, at the most 90 minutes, at themost 80 minutes, at the most 70 minutes, at the most 60 minutes, at themost 50 minutes, at the most 40 minutes, at the most 30 minutes, at themost 20 minutes, or at the most 15 minutes under fasting conditions.

In an embodiment of the invention, the formulation according to theinvention comprises an enteric coating and the in vivo release of thefumaric acid ester displays a lag time of 15 minutes to 2 hours underfasting conditions, such as a lag time of at the most 120 minutes, atthe most 110 minutes, at the most 100 minutes, at the most 90 minutes,at the most 80 minutes, at the most 70 minutes, at the most 60 minutes,at the most 50 minutes, at the most 40 minutes, at the most 30 minutes,at the most 20 minutes, or at the most 15 minutes under fastingconditions.

In an embodiment of the invention, the release of the fumaric acidester—when subjected to an in vitro dissolution test employing 0.1 Nhydrochloric acid as dissolution medium during the first 2 hours of thetest and then 0.05 M phosphate buffer pH 6.8 as dissolution medium—is asfollows:

within the first 2 hours after start of the test from about 0% w/w toabout 50% w/w of the fumaric ester contained in the formulation isreleased, and/or

within the first 3 hours after start of the test from about 20% w/w toabout 75% w/w of the total amount of the fumaric acid ester contained inthe formulation is released.

In an embodiment of the invention, the release of the fumaric acidester—when subjected to an in vitro dissolution test employing 0.1 Nhydrochloric acid as dissolution medium during the first 2 hours of thetest and then 0.05 M phosphate buffer pH 6.8 as dissolution medium—is asfollows:

within the first 3.5 hours after start of the test at the most about 95%w/w of the total amount of the fumaric acid ester contained in theformulation is released.

In an embodiment of the invention, the release of the fumaric acidester—when subjected to an in vitro dissolution test employing 0.1 Nhydrochloric acid as dissolution medium during the first 2 hours of thetest and then 0.05 M phosphate buffer pH 6.8 as dissolution medium—is asfollows:

within the first 4 hours after start of the test at the most about 98%w/w of the total amount of the fumaric acid ester contained in theformulation is released.

In an embodiment of the invention the release of the fumaric acidester—when subjected to an in vitro dissolution test employing 0.1 Nhydrochloric acid as dissolution medium during the first 2 hours of thetest and then 0.05 M phosphate buffer pH 6.8 as dissolution medium—is asfollows:

within the first 2 hours after start of the test from about 0% w/w toabout 60% w/w, such as about 0% w/w to about 50% w/w, such as about 0%w/w to about 40% w/w, such as about 0% w/w to about 30%, such as about0% w/w to about 20%, such as about 0% w/w to about 10%, such as about 0%w/w to about 5%, such as about 0% w/w of the fumaric ester contained inthe formulation is released, and/or

within the first 3 hours after start of the test from about 15% w/w toabout 95% w/w, such as about 20% w/w to about 95% w/w, such as about 20%w/w to about 75% w/w, such as about 25% w/w to about 75% w/w, such asabout 40% w/w to about 95% w/w, such as about 40% w/w to about 75% w/w,such as about 50% w/w to about 95% w/w, such as about 50% w/w to about75%, such as about 60% w/w to about 95% w/w, such as about 60% w/w toabout 75%, such as about 70% w/w to about 95%, such as about 80% w/w toabout 95%, such as about 90% w/w to about 95% of the total amount of thefumaric acid ester contained in the formulation is released.

In an embodiment of the invention the release of the fumaric acidester—when subjected to an in vitro dissolution test employing 0.1 Nhydrochloric acid as dissolution medium during the first 2 hours of thetest and then 0.05 M phosphate buffer pH 6.8 as dissolution medium—is asfollows:

within the first 2 hours after start of the test from about 0% w/w toabout 60% w/w, such as about 0% w/w to about 5% w/w, such as about 0%w/w to about 10% w/w, or such as about 15% w/w to about 35% w/w, or suchas about 35% w/w to about 55% w/w of the fumaric ester contained in theformulation is released, and/or

within the first 3 hours after start of the test from about 15% w/w toabout 95% w/w, such as about 15% w/w to about 75% w/w, such as about 20%w/w to about 75% w/w, such as about 15% w/w to about 35% w/w, or such asabout 35% w/w to about 55% w/w, or such as about 55% w/w to about 75%,or such as about 65% w/w to about 85%, or such as about 70% w/w to about80%, or such as about 75% w/w to about 95%, or such as about 85% w/w toabout 95% of the total amount of the fumaric acid ester contained in theformulation is released.

In an embodiment of the invention the release of the fumaric acidester—when subjected to an in vitro dissolution test employing 0.1 Nhydrochloric acid as dissolution medium during the first 2 hours of thetest and then 0.05 M phosphate buffer pH 6.8 as dissolution medium—is asfollows:

within the first 2 hours after start of the test from about 1% w/w toabout 25% w/w of the fumaric ester contained in the formulation isreleased, and/or

within the first 3 hours after start of the test from about 15% w/w toabout 95% w/w, such as about 15% w/w to about 75% w/w, such as about 25%w/w to about 95% w/w, such as about 25% w/w to about 75% w/w, such asabout 40% w/w to about 95% w/w, such as about 40% w/w to about 75% w/w,such as about 50% w/w to about 95% w/w, such as about 50% w/w to about75%, such as about 60% w/w to about 95% w/w, such as about 60% w/w toabout 75%, such as about 70% w/w to about 95% w/w, such as about 80% w/wto about 95% w/w, such as about 90% w/w to about 95% w/w of the totalamount of the fumaric acid ester contained in the formulation isreleased.

In an embodiment of the invention the release of the fumaric acidester—when subjected to an in vitro dissolution test employing 0.1 Nhydrochloric acid as dissolution medium during the first 2 hours of thetest and then 0.05 M phosphate buffer pH 6.8 as dissolution medium—is asfollows:

within the first 2 hours after start of the test from about 1% w/w toabout 25% w/w of the fumaric ester contained in the formulation isreleased, and/or

within the first 3 hours after start of the test from about 15% w/w toabout 95% w/w, such as about 15% w/w to about 75% w/w, such as about 15%w/w to about 35% w/w, or such as about 35% w/w to about 55% w/w, or suchas about 55% w/w to about 75%, or such as about 65% w/w to about 85%, orsuch as about 70% w/w to about 80%, or such as about 75% w/w to about95%, or such as about 85% w/w to about 95% of the total amount of thefumaric acid ester contained in the formulation is released.

In an embodiment of the invention the release of the fumaric acidester—when subjected to an in vitro dissolution test employing 0.1 Nhydrochloric acid as dissolution medium during the first 2 hours of thetest and then 0.05 M phosphate buffer pH 6.8 as dissolution medium—is asfollows:

within the first 3.5 hours after start of the test at the most about100% w/w, such as about 30% w/w to about 100% w/w, such as about 30% w/wto about 95% w/w, such as about 40% w/w to about 100% w/w, such as about40% w/w to about 95% w/w, such as about 50% w/w to about 100% w/w, suchas about 50% w/w to about 95%, such as about 60% w/w to about 100% w/w,such as about 60% w/w to about 95%, such as about 70% w/w to about 100%w/w, such as about 70% w/w to about 95%, such as about 80% w/w to about100% w/w, such as about 80% w/w to about 95%, such as about 90% w/w toabout 100% w/w, such as about 90% w/w to about 95% w/w of the totalamount of the fumaric acid ester contained in the formulation isreleased.

In an embodiment of the invention the release of the fumaric acidester—when subjected to an in vitro dissolution test employing 0.1 Nhydrochloric acid as dissolution medium during the first 2 hours of thetest and then 0.05 M phosphate buffer pH 6.8 as dissolution medium—is asfollows:

within the first 3.5 hours after start of the test at the most about100% w/w, such as about 30% w/w to about 90% w/w, such as about 30% w/wto about 50% w/w, or such as about 60% w/w to about 80%, or such asabout 80% w/w to about 95% of the total amount of the fumaric acid estercontained in the formulation is released.

In an embodiment of the invention the release of the fumaric acidester—when subjected to an in vitro dissolution test employing 0.1 Nhydrochloric acid as dissolution medium during the first 2 hours of thetest and then 0.05 M phosphate buffer pH 6.8 as dissolution medium—is asfollows:

within the first 4 hours after start of the test at the most about 100%w/w, such as about 35% w/w to about 100% w/w, such as about 35% w/w toabout 98% w/w, such as about 40% w/w to about 100% w/w, such as about40% w/w to about 98% w/w, such as about 50% w/w to about 100% w/w, suchas about 50% w/w to about 98%, such as about 60% w/w to about 100% w/w,such as about 60% w/w to about 98%, such as about 70% w/w to about 100%w/w, such as about 70% w/w to about 98%, such as about 80% w/w to about100% w/w, such as about 80% w/w to about 98%, such as about 90% w/w toabout 100% w/w, such as about 90% w/w to about 98% of the total amountof the fumaric acid ester contained in the formulation is released.

In an embodiment of the invention the release of the fumaric acidester—when subjected to an in vitro dissolution test employing 0.1 Nhydrochloric acid as dissolution medium during the first 2 hours of thetest and then 0.05 M phosphate buffer pH 6.8 as dissolution medium—is asfollows:

within the first 4 hours after start of the test at the most about 100%w/w, such as about 35% w/w to about 98% w/w, such as about 50% w/w toabout 70%, or such as about 85% w/w to about 95% w/w of the total amountof the fumaric acid ester contained in the formulation is released.

In an embodiment of the invention the release of the fumaric acidester—when subjected to an in vitro dissolution test employing 0.1 Nhydrochloric acid as dissolution medium during the first 2 hours of thetest and then 0.05 M phosphate buffer pH 6.8 as dissolution medium—is asfollows:

within the first 4 hours after start of the test at the most about 95%w/w, such as at the most about 90% w/w, such as at the most about 70% ofthe total amount of the fumaric acid ester contained in the formulationis released.

In an embodiment of the invention the release of the fumaric acidester—when subjected to an in vitro dissolution test employing 0.1 Nhydrochloric acid as dissolution medium during the first 2 hours of thetest and then 0.05 M phosphate buffer pH 6.8 as dissolution medium—is asfollows:

within the first 2 hours after start of the test from about 0% w/w toabout 5% w/w of the total amount of the fumaric ester contained in theformulation is released, and

within the first 3 hours after start of the test from about 15% w/w toabout 35% w/w of the total amount of the fumaric acid ester contained inthe formulation is released; and

within the first 3.5 hours after start of the test from about 30% w/w toabout 50% w/w of the total amount of the fumaric acid ester contained inthe formulation is released; and

within the first 4 hours after start of the test from about 50% w/w toabout 70% w/w of the total amount of the fumaric acid ester contained inthe formulation is released.

In an embodiment of the invention the release of the fumaric acidester—when subjected to an in vitro dissolution test employing 0.1 Nhydrochloric acid as dissolution medium during the first 2 hours of thetest and then 0.05 M phosphate buffer pH 6.8 as dissolution medium—is asfollows:

within the first 2 hours after start of the test from about 0% w/w toabout 5% w/w of the total amount of the fumaric ester contained in theformulation is released, and

within the first 3 hours after start of the test from about 15% w/w toabout 35% w/w of the total amount of the fumaric acid ester contained inthe formulation is released; and

within the first 3.5 hours after start of the test from about 30% w/w toabout 50% w/w of the total amount of the fumaric acid ester contained inthe formulation is released; and

within the first 4 hours after start of the test from about 50% w/w toabout 70% w/w of the total amount of the fumaric acid ester contained inthe formulation is released; and

within the first 5 hours after start of the test from about 70% w/w toabout 100% w/w of the total amount of the fumaric acid ester containedin the formulation is released.

In an embodiment of the invention the release of the fumaric acidester—when subjected to an in vitro dissolution test employing 0.1 Nhydrochloric acid as dissolution medium during the first 2 hours of thetest and then 0.05 M phosphate buffer pH 6.8 as dissolution medium—is asfollows:

within the first 2 hours after start of the test from about 0% w/w toabout 5% w/w of the total amount of the fumaric ester contained in theformulation is released, and

within the first 3 hours after start of the test from about 30% w/w toabout 55% w/w of the total amount of the fumaric acid ester contained inthe formulation is released; and

within the first 3.5 hours after start of the test from about 60% w/w toabout 80% w/w of the total amount of the fumaric acid ester contained inthe formulation is released; and

within the first 4 hours after start of the test from about 80% w/w toabout 95% w/w of the total amount of the fumaric acid ester contained inthe formulation is released.

In an embodiment of the invention the release of the fumaric acidester—when subjected to an in vitro dissolution test employing 0.1 Nhydrochloric acid as dissolution medium during the first 2 hours of thetest and then 0.05 M phosphate buffer pH 6.8 as dissolution medium—is asfollows:

within the first 2 hours after start of the test from about 0% w/w toabout 5% w/w of the total amount of the fumaric ester contained in theformulation is released, and

within the first 3 hours after start of the test from about 30% w/w toabout 55% w/w of the total amount of the fumaric acid ester contained inthe formulation is released; and

within the first 3.5 hours after start of the test from about 60% w/w toabout 80% w/w of the total amount of the fumaric acid ester contained inthe formulation is released; and

within the first 4 hours after start of the test from about 80% w/w toabout 95% w/w of the total amount of the fumaric acid ester contained inthe formulation is released; and

within the first 5 hours after start of the test from about 80% w/w toabout 100% w/w of the total amount of the fumaric acid ester containedin the formulation is released.

In an embodiment of the invention the release of the fumaric acidester—when subjected to an in vitro dissolution test employing 0.1 Nhydrochloric acid as dissolution medium during the first 2 hours of thetest and then 0.05 M phosphate buffer pH 6.8 as dissolution medium—is asfollows:

within the first 2 hours after start of the test from about 0% w/w toabout 5% w/w of the total amount of the fumaric ester contained in theformulation is released, and

within the first 3 hours after start of the test from about 60% w/w toabout 85% w/w of the total amount of the fumaric acid ester contained inthe formulation is released; and

within the first 3.5 hours after start of the test from about 80% w/w toabout 95% w/w of the total amount of the fumaric acid ester contained inthe formulation is released; and

within the first 4 hours after start of the test from about 85% w/w toabout 100% w/w of the total amount of the fumaric acid ester containedin the formulation is released.

In an embodiment of the invention the release of the fumaric acidester—when subjected to an in vitro dissolution test employing 0.1 Nhydrochloric acid as dissolution medium during the first 2 hours of thetest and then 0.05 M phosphate buffer pH 6.8 as dissolution medium—is asfollows:

within the first 2 hours after start of the test from about 0% w/w toabout 5% w/w of the total amount of the fumaric ester contained in theformulation is released, and

within the first 3 hours after start of the test from about 60% w/w toabout 85% w/w of the total amount of the fumaric acid ester contained inthe formulation is released; and

within the first 3.5 hours after start of the test from about 80% w/w toabout 100% w/w of the total amount of the fumaric acid ester containedin the formulation is released; and

within the first 4 hours after start of the test from about 85% w/w toabout 100% w/w of the total amount of the fumaric acid ester containedin the formulation is released.

In an embodiment of the invention the release of the fumaric acidester—when subjected to an in vitro dissolution test employing 0.1 Nhydrochloric acid as dissolution medium during the first 2 hours of thetest and then 0.05 M phosphate buffer pH 6.8 as dissolution medium—is asfollows:

within the first 2 hours after start of the test from about 15% w/w toabout 35% w/w of the fumaric ester contained in the formulation isreleased, and

within the first 3 hours after start of the test from about 55% w/w toabout 80% w/w of the total amount of the fumaric acid ester contained inthe formulation is released; and

within the first 3.5 hours after start of the test from about 70% w/w toabout 90% w/w of the total amount of the fumaric acid ester contained inthe formulation is released; and

within the first 4 hours after start of the test from about 80% w/w toabout 100% w/w of the total amount of the fumaric acid ester containedin the formulation is released.

In an embodiment of the invention the release of the fumaric acidester—when subjected to an in vitro dissolution test employing 0.1 Nhydrochloric acid as dissolution medium during the first 2 hours of thetest and then 0.05 M phosphate buffer pH 6.8 as dissolution medium—is asfollows:

within the first 2 hours after start of the test from about 0% w/w toabout 5% w/w of the total amount of the fumaric ester contained in theformulation is released, and

within the first 3 hours after start of the test from about 10% w/w toabout 30% w/w of the total amount of the fumaric acid ester contained inthe formulation is released; and

within the first 3.5 hours after start of the test from about 15% w/w toabout 40% w/w of the total amount of the fumaric acid ester contained inthe formulation is released; and

within the first 4 hours after start of the test from about 30% w/w toabout 50% w/w of the total amount of the fumaric acid ester contained inthe formulation is released.

In an embodiment of the invention the release of the fumaric acidester—when subjected to an in vitro dissolution test employing 0.1 Nhydrochloric acid as dissolution medium during the first 2 hours of thetest and then 0.05 M phosphate buffer pH 6.8 as dissolution medium—is asfollows:

within the first 2 hours after start of the test from about 0% w/w toabout 5% w/w of the total amount of the fumaric ester contained in theformulation is released, and

within the first 3 hours after start of the test from about 10% w/w toabout 30% w/w of the total amount of the fumaric acid ester contained inthe formulation is released; and

within the first 3.5 hours after start of the test from about 15% w/w toabout 40% w/w of the total amount of the fumaric acid ester contained inthe formulation is released; and

within the first 4 hours after start of the test from about 30% w/w toabout 50% w/w of the total amount of the fumaric acid ester contained inthe formulation is released; and

within the first 6 hours after start of the test from about 75% w/w toabout 100% w/w of the total amount of the fumaric acid ester containedin the formulation is released.

In an embodiment of the invention the release of the fumaric acidester—when subjected to an in vitro dissolution test employing 0.1 Nhydrochloric acid as dissolution medium during the first 2 hours of thetest and then 0.05 M phosphate buffer pH 6.8 as dissolution medium—is asfollows:

within the first 2 hours after start of the test from about 0% w/w toabout 5% w/w of the total amount of the fumaric ester contained in theformulation is released, and

within the first 3 hours after start of the test from about 5% w/w toabout 25% w/w of the total amount of the fumaric acid ester contained inthe formulation is released; and

within the first 3.5 hours after start of the test from about 10% w/w toabout 30% w/w of the total amount of the fumaric acid ester contained inthe formulation is released; and

within the first 4 hours after start of the test from about 20% w/w toabout 40% w/w of the total amount of the fumaric acid ester contained inthe formulation is released.

In an embodiment of the invention the release of the fumaric acidester—when subjected to an in vitro dissolution test employing 0.1 Nhydrochloric acid as dissolution medium during the first 2 hours of thetest and then 0.05 M phosphate buffer pH 6.8 as dissolution medium—is asfollows:

within the first 2 hours after start of the test from about 0% w/w toabout 5% w/w of the total amount of the fumaric ester contained in theformulation is released, and

within the first 3 hours after start of the test from about 5% w/w toabout 25% w/w of the total amount of the fumaric acid ester contained inthe formulation is released; and

within the first 3.5 hours after start of the test from about 10% w/w toabout 30% w/w of the total amount of the fumaric acid ester contained inthe formulation is released; and

within the first 4 hours after start of the test from about 20% w/w toabout 40% w/w of the total amount of the fumaric acid ester contained inthe formulation is released; and

within the first 5 hours after start of the test from about 30% w/w toabout 50% w/w of the total amount of the fumaric acid ester contained inthe formulation is released.

In an embodiment of the invention the release of the fumaric acidester—when subjected to an in vitro dissolution test employing 0.1 Nhydrochloric acid as dissolution medium during the first 2 hours of thetest and then 0.05 M phosphate buffer pH 6.8 as dissolution medium—is asfollows:

within the first 2 hours after start of the test from about 0% w/w toabout 5% w/w of the total amount of the fumaric ester contained in theformulation is released, and

within the first 3 hours after start of the test from about 2% w/w toabout 20% w/w of the total amount of the fumaric acid ester contained inthe formulation is released; and

within the first 3.5 hours after start of the test from about 5% w/w toabout 20% w/w of the total amount of the fumaric acid ester contained inthe formulation is released; and

within the first 4 hours after start of the test from about 5% w/w toabout 25% w/w of the total amount of the fumaric acid ester contained inthe formulation is released.

In an embodiment of the invention the release of the fumaric acidester—when subjected to an in vitro dissolution test employing 0.1 Nhydrochloric acid as dissolution medium during the first 2 hours of thetest and then 0.05 M phosphate buffer pH 6.8 as dissolution medium—is asfollows:

within the first 2 hours after start of the test from about 0% w/w toabout 5% w/w of the total amount of the fumaric ester contained in theformulation is released, and

within the first 3 hours after start of the test from about 2% w/w toabout 20% w/w of the total amount of the fumaric acid ester contained inthe formulation is released; and

within the first 3.5 hours after start of the test from about 5% w/w toabout 20% w/w of the total amount of the fumaric acid ester contained inthe formulation is released; and

within the first 4 hours after start of the test from about 5% w/w toabout 25% w/w of the total amount of the fumaric acid ester contained inthe formulation is released; and

within the first 5 hours after start of the test from about 10% w/w toabout 30% w/w of the total amount of the fumaric acid ester contained inthe formulation is released.

In an embodiment of the invention the release has zero order, firstorder or square-root (Higuchi's) kinetics release profile.

In a further embodiment the in vitro release has a combination of zeroorder, first order and square-root (Higuchi's) kinetics in vitro releaseprofiles, e.g. a combination of zero and first order in vitro releaseprofiles.

Different kinetic models, such as zero-order (1), first-order (2),square-root (Higuchi's equation) (3) can be applied to theinterpretation of the drug release kinetic.

M _(t) =M ₀ +k ₀ *t  1:

ln M _(t)=ln M+k ₁ *t  2:

M _(t) =M ₀ +k _(H) *t ^(1/2)  3:

In these equations, M_(t) is the cumulative amount of drug released atany specified time point and M₀ is the dose of active substanceincorporated in the pharmaceutical compostion. k₀, k₁ and k_(H) are rateconstants for zero-order, first-order and Higuchi's equation,respectively.

One aspect of the invention relates to a zero-order dissolution releaseprofile. Another aspect relates to a first-order dissolution releaseprofile. A further aspect relates to a square-root (Higuchi's equation)dissolution release profile.

The active substance in a formulation of the invention is any fumaricacid ester.

In one embodiment of the invention the fumaric acid ester is preferablyselected from the group consisting of dimethylfumarate, diethylfumarate,dipropylfumarate, dibutylfumarate, dipentylfumarate,methyl-ethylfumarate, methyl-propylfumarate, methyl-butylfumarate,methyl-pentylfumarate, monomethylfumarate, monoethylfumarate,monopropylfumarate, monobutylfumarate and monopentylfumarate, includingpharmaceutically acceptable salts thereof.

Pharmaceutically acceptable salts thereof comprise metal salts, such asa salt selected from alkali metal salts and alkaline earth metal saltsincluding sodium, potassium, calcium, magnesium, strontium or zincsalts, amino acid salts etc.

In another embodiment of the invention the fumaric acid ester is presentin the form of a monosaccharide ester thereof such as e.g. described inEP06753340.6.

In another embodiment of the invention the fumaric acid ester is presentin the form of an amino acid salt thereof. The amino acid may be anaturally occurring amino acid such as glycine, alanine, valine,norvaline, isovaline, leucine, norleucine, isoleucine, methionine,phenylalanine, tryptophan, serine, thereonine, cysteine, penicillamine,tyrosine, asparagine, glutamine, aspartic acid, glutamic acid,ornithine, lysine, arginine, histidine, proline, 4-hydroxproline andpipecolic acid.

In a specific embodiment of the invention, the fumaric acid ester is amono-(C₁-C₅)alkylester of fumaric acid that is present in the form of apharmaceutically acceptable salt. Suitable salts are e.g. metal saltssuch as a salt selected from alkali metal salts and alkaline earth metalsalts including sodium, potassium, calcium, magnesium, strontium or zincsalt.

The term (C₁-C₅) alkyl refers to a branched or un-branched alkyl grouphaving from one to five carbon atoms inclusive, such as methyl, ethyl,1-propyl, 2-propyl, 1-butyl, 2-butyl, 2-methyl-2-propyl,2-methyl-1-propyl and pentyl.

In another embodiment, the formulation according to the inventioncomprises dimethylfumarate as the active substance.

In a further embodiment, the formulation according to the inventioncomprises monomethylfumarate as the active substance optionally in theform of a pharmaceutically acceptable salt like e.g. its sodium,potassium, calcium, magnesium, strontium and/or zinc salt.

In a further embodiment, the formulation according to the inventioncomprises monomethylfumarate as the active substance optionally in theform of an amino acid salt thereof.

In another embodiment, the formulation according to the inventionconsists essentially of dimethylfumarate as the active substance.

In another embodiment, the formulation according to the inventionconsists of dimethylfumarate as the active substance.

In a further embodiment, the formulation according to the inventionconsists essentially of monomethylfumarate as the active substanceoptionally in the form of a pharmaceutically acceptable salt like e.g.its sodium, potassium, calcium, magnesium, strontium and/or zinc salt.

In a further embodiment, the formulation according to the inventionconsists of monomethylfumarate as the active substance optionally in theform of a pharmaceutically acceptable salt like e.g. its sodium,potassium, calcium, magnesium, strontium and/or zinc salt.

In a further embodiment, the formulation according to the inventioncomprises dimethylfumarate and monomethylfumarate (optionally in theform of a pharmaceutically acceptable salt like e.g. its sodium,potassium, calcium, magnesium, strontium and/or zinc salt) as the activesubstances, in a weight ratio between about 1:10 and about 10:1.

In a further embodiment, the formulation according to the inventionconsists essentially of dimethylfumarate and monomethylfumarate(optionally in the form of a pharmaceutically acceptable salt like e.g.its sodium, potassium, calcium, magnesium, strontium and/or zinc salt)as the active substances, in a weight ratio between about 1:10 and about10:1.

In a further embodiment, the formulation according to the inventionconsists of dimethylfumarate and monomethylfumarate (optionally in theform of a pharmaceutically acceptable salt like e.g. its sodium,potassium, calcium, magnesium, strontium and/or zinc salt) as the activesubstances, in a weight ratio between about 1:10 and about 10:1.

In an embodiment the formulation according to the invention is foradministration once, twice or three times daily.

In an embodiment the formulation is for administration once daily.

In an embodiment the formulation is for administration twice daily.

The daily dosage of the controlled release pharmaceutical formulationaccording to the invention that is administered to treat a patientdepends on a number of factors among which are included, withoutlimitation, weight and age and the underlying causes of the condition ordisease to be treated, and is within the skill of a physician todetermine.

In one aspect of the invention the daily dosage can be e.g. from 200 to400 mg active substance given in one to three doses, in another aspectfrom 300 to 500 mg active substance given in one to three doses, inanother aspect 400 to 600 mg active substance given in one to threedoses, in another aspect 500 to 700 mg active substance given in one tothree doses, in another aspect 600 to 800 mg active substance given inone to three doses, in another aspect 700 to 900 mg active substancegiven in one to three doses, in another aspect 800 to 1000 mg activesubstance given in one to three doses, in another aspect 900 to 1100 mgactive substance given in one to three doses, in another aspect 1000 to1200 mg active substance given in one to three doses, in another aspect1100 to 1300 mg active substance given in one to three doses, in anotheraspect 1200 to 1400 mg active substance given in one to three doses andin yet another aspect 1300 to 2000 mg active substance given in one tothree doses.

An embodiment of the invention is a pharmaceutical formulationcomprising:

-   -   i) 40% to 55% by weight of dimethyl fumarate;    -   ii) 4-6% by weight of hydroxypropyl cellulose;    -   iii) 35-55% by weight of lactose.

An embodiment of the invention is a pharmaceutical formulationcomprising:

-   -   i) 30% to 60% by weight of dimethyl fumarate;    -   ii) 3-6% by weight of hydroxypropyl cellulose;    -   iii) 35-65% by weight of lactose.

An embodiment of the invention is a pharmaceutical formulation in theform of an erosion matrix tablet comprising:

-   -   A) A tablet core comprising:        -   i) 40-60% by weight of one or more fumaric acid esters            selected from di-(C₁-C₅)alkylesters of fumaric acid and            mono-(C₁-C₅)alkylesters of fumaric acid, or a            pharmaceutically acceptable salt thereof, as an active            substance,        -   ii) 4-6% by weight of a rate-controlling agent;        -   iii) 35-55% by weight of a binder;    -   B) an enteric coating in an amount of about 1.5-3.5% by weight        of the core;

wherein erosion of said erosion matrix results in release of the fumaricacid ester—when subjected to an in vitro dissolution test employing 0.1N hydrochloric acid as dissolution medium during the first 2 hours ofthe test and then 0.05 M phosphate buffer pH 6.8 as dissolutionmedium—as follows:

within the first 2 hours after start of the test from about 0% w/w toless than about 10% w/w of the fumaric ester contained in theformulation is released, and/or

within the first 3 hours after start of the test from about 20% w/w toabout 75% w/w of the fumaric ester contained in the formulation isreleased, and/or

within the first 4 hours after start of the test from about 5⁰% w/w toabout 98% w/w of the fumaric ester contained in the formulation isreleased, and/or

within the first 5 hours after start of the test from about 70% w/w toabout 100% w/w of the total amount of the fumaric acid ester containedin the formulation is released.

An embodiment of the invention is a pharmaceutical formulation in theform of an erosion matrix tablet comprising:

-   -   A) A tablet core comprising:        -   i) 30-60% by weight of one or more fumaric acid esters            selected from di-(C₁-C₅)alkylesters of fumaric acid and            mono-(C₁-C₅)alkylesters of fumaric acid, or a            pharmaceutically acceptable salt thereof, as an active            substance,        -   ii) 3-6% by weight of a rate-controlling agent;        -   iii) 35-65% by weight of a binder;    -   B) an enteric coating in an amount of about 1.5-3.5% by weight        of the core;

wherein erosion of said erosion matrix results in release of the fumaricacid ester—when subjected to an in vitro dissolution test employing 0.1N hydrochloric acid as dissolution medium during the first 2 hours ofthe test and then 0.05 M phosphate buffer pH 6.8 as dissolutionmedium—as follows:

within the first 2 hours after start of the test from about 0% w/w toless than about 10% w/w of the fumaric ester contained in theformulation is released, and/or

within the first 3 hours after start of the test from about 20% w/w toabout 75% w/w of the fumaric ester contained in the formulation isreleased, and/or

within the first 4 hours after start of the test from about 5⁰% w/w toabout 98% w/w of the fumaric ester contained in the formulation isreleased, and/or

within the first 5 hours after start of the test from about 70% w/w toabout 100% w/w of the total amount of the fumaric acid ester containedin the formulation is released.

An embodiment of the invention is a pharmaceutical formulation in theform of a monolithic erosion matrix tablet comprising:

-   -   A) A tablet core comprising:        -   i) 40-60% by weight of one or more fumaric acid esters            selected from di-(C₁-C₅)alkylesters of fumaric acid and            mono-(C₁-C₅)alkylesters of fumaric acid, or a            pharmaceutically acceptable salt thereof, as an active            substance,        -   ii) 4-6% by weight of a rate-controlling agent;        -   iii) 35-55% by weight of a binder;    -   B) an enteric coating in an amount of about 1.5-3.5% by weight        of the core;

wherein erosion of said erosion matrix results in release of the fumaricacid ester—when subjected to an in vitro dissolution test employing 0.1N hydrochloric acid as dissolution medium during the first 2 hours ofthe test and then 0.05 M phosphate buffer pH 6.8 as dissolutionmedium—as follows:

within the first 2 hours after start of the test from about 0% w/w toless than about 10% w/w of the fumaric ester contained in theformulation is released, and/or

within the first 3 hours after start of the test from about 20% w/w toabout 75% w/w of the fumaric ester contained in the formulation isreleased, and/or

within the first 4 hours after start of the test from about 50% w/w toabout 98% w/w of the fumaric ester contained in the formulation isreleased, and/or

within the first 5 hours after start of the test from about 70% w/w toabout 100% w/w of the total amount of the fumaric acid ester containedin the formulation is released.

An embodiment of the invention is a pharmaceutical formulation in theform of a monolithic erosion matrix tablet comprising:

-   -   A) A tablet core comprising:        -   i) 30-60% by weight of one or more fumaric acid esters            selected from di-(C₁-C₅)alkylesters of fumaric acid and            mono-(C₁-C₅)alkylesters of fumaric acid, or a            pharmaceutically acceptable salt thereof, as an active            substance,        -   ii) 3-6% by weight of a rate-controlling agent;        -   iii) 35-65% by weight of a binder;    -   B) an enteric coating in an amount of about 1.5-3.5% by weight        of the core;

wherein erosion of said erosion matrix results in release of the fumaricacid ester—when subjected to an in vitro dissolution test employing 0.1N hydrochloric acid as dissolution medium during the first 2 hours ofthe test and then 0.05 M phosphate buffer pH 6.8 as dissolutionmedium—as follows:

within the first 2 hours after start of the test from about 0% w/w toless than about 10% w/w of the fumaric ester contained in theformulation is released, and/or

within the first 3 hours after start of the test from about 20% w/w toabout 75% w/w of the fumaric ester contained in the formulation isreleased, and/or

within the first 4 hours after start of the test from about 50% w/w toabout 98% w/w of the fumaric ester contained in the formulation isreleased, and/or

within the first 5 hours after start of the test from about 70% w/w toabout 100% w/w of the total amount of the fumaric acid ester containedin the formulation is released.

An embodiment of the invention is a pharmaceutical formulation in theform of an erosion matrix tablet comprising:

-   -   A) A tablet core comprising:        -   i) 40-55% by weight of dimethyl fumarate,        -   ii) 4-6% by weight of hydroxypropyl cellulose;        -   iii) 35-55% by weight of lactose;    -   B) an enteric coating in an amount of about 1.5-3.5% by weight        of the core;

wherein erosion of said erosion matrix results in release of thedimethyl fumarate—when subjected to an in vitro dissolution testemploying 0.1 N hydrochloric acid as dissolution medium during the first2 hours of the test and then 0.05 M phosphate buffer pH 6.8 asdissolution medium—as follows:

within the first 2 hours after start of the test from about 0% w/w toless than about 10% w/w of the dimethyl fumarate contained in theformulation is released, and/or

within the first 3 hours after start of the test from about 20% w/w toabout 75% w/w of the dimethyl fumarate contained in the formulation isreleased, and/or

within the first 4 hours after start of the test from about 50% w/w toabout 98% w/w of the fumaric ester contained in the formulation isreleased, and/or

within the first 5 hours after start of the test from about 70% w/w toabout 100% w/w of the total amount of the dimethyl fumarate contained inthe formulation is released.

An embodiment of the invention is a pharmaceutical formulation in theform of a monolithic erosion matrix tablet comprising:

-   -   A) A tablet core comprising:        -   i) 40-55% by weight of dimethyl fumarate,        -   ii) 4-6% by weight of hydroxypropyl cellulose;        -   iii) 35-55% by weight of lactose;    -   B) an enteric coating in an amount of about 1.5-3.5% by weight        of the core;

wherein erosion of said erosion matrix results in release of thedimethyl fumarate—when subjected to an in vitro dissolution testemploying 0.1 N hydrochloric acid as dissolution medium during the first2 hours of the test and then 0.05 M phosphate buffer pH 6.8 asdissolution medium—as follows:

within the first 2 hours after start of the test from about 0% w/w toless than about 10% w/w of the dimethyl fumarate contained in theformulation is released, and/or

within the first 3 hours after start of the test from about 20% w/w toabout 75% w/w of the dimethyl fumarate contained in the formulation isreleased, and/or

within the first 4 hours after start of the test from about 50% w/w toabout 98% w/w of the fumaric ester contained in the formulation isreleased, and/or

within the first 5 hours after start of the test from about 70% w/w toabout 100% w/w of the total amount of the dimethyl fumarate contained inthe formulation is released.

Preparation of the erosion matrix tablets according to the invention maybe obtained by granulation, followed by tabletting and optionally filmand/or enteric coating of the core tablets obtained. The core can forexample be made by conventional wet granulation or continuousgranulation such as extrusion followed by compaction of the granulesinto tablets.

The core may then be coated using an appropriate technology, preferablyby air suspension.

An aspect of the invention is a method for preparing the formulationaccording to the invention, comprising the steps of:

-   -   a) Dissolving (or suspending) either one or both of a fumaric        acid ester and optionally a rate-controlling agent in the form        of a polymeric matrix material in water to obtain an aqueous        suspension thereof;    -   b) Spraying said aqueous suspension on granules of a fumaric        acid ester and/or a binder for a period of time sufficient to        obtain a uniform coating thereon;    -   c) Drying the granules obtained;    -   d) Optionally sieving or milling said granules;    -   e) Blending of any pharmaceutically acceptable excipients and        additives in a manner known per se to obtain a tablet        formulation;    -   f) Optionally film and/or enteric coating of said tablet        formulation in a manner known per se;

wherein any of or all of the above steps are performed at a temperatureto allow a product temperature not exceeding 45° C. In an embodiment ofthe invention any of or all of the above steps are performed at atemperature to allow a product temperature not exceeding 40° C., such asnot exceeding 35° C., such as not exceeding 30° C. Thus it hassurprisingly been shown that the preparation of the formulationaccording to the invention may be obtained by the use of solely water assolvent, thus obviating the need for any organic solvents. Furthermoreall process steps may be carried out at a rather low temperature.Thereby any sublimation of the active pharmaceutical ingredient isminimised or reduced and an energy-efficient process is obtained,mitigating loss of API, thus reducing cost as well as improvingenvironmental and workers' safety.

In the present context particle size is measured by conventional sieveanalysis known to the person skilled in the art.

In an embodiment of the invention the fumaric acid ester is micronizedto obtain a particle size, wherein at least 90% of the particles have aparticle size of at most 50 μm, such as at most 30 μm, such as at most10 μm, prior to step a) above.

In another embodiment, the mean particle size of the activepharmaceutical ingredient (the fumaric acid ester(s)) is reduced, e.g.by sieving or milling, such that at least 50% of the particles have aparticle size of less than 800 μm, such as less than 600 μm, such asless than 500 μm, such as less than 400 μm, such as less than 200 μm,prior to step a) above.

In another embodiment, the mean particle size of the activepharmaceutical ingredient (the fumaric acid ester(s)) is reduced, e.g.by sieving or milling, such that at least 80% of the particles have aparticle size of less than 800 μm, such as less than 600 μm, such asless than 500 μm, such as less than 400 μm, such as less than 200 μm,prior to step a) above.

In another embodiment, the mean particle size of the activepharmaceutical ingredient (the fumaric acid ester(s)) is reduced, e.g.by sieving or milling, such that at least 90% of the particles have aparticle size of less than 800 μm, such as less than 600 μm, such asless than 500 μm, such as less than 400 μm, such as less than 200 μm,prior to step a) above.

In another embodiment, crystals of fumaric acid ester are sieved ormilled such that 90% of the particles have a particle size in the rangeof 5-1000 μm, such as in the range of 10-900 μm, such as in the range of20-800 μm, such as in the range of 30-750 μm, such as in the range of40-600 μm, such as in the range of 50-500 μm, such as in the range of100-400 μm, such as in the range of 200-300 μm, such as in the range of300-600 μm, such as in the range of 300-400 μm, such as in the range of400-600 μm or such as in the range of 500-600 μm, prior to step a)above.

In another embodiment, the mean particle size of the activepharmaceutical ingredient (the fumaric acid ester(s)) is in the range of5-1000 μm, such as in the range of 10-900 μm, such as in the range of20-800 μm, such as in the range of 30-750 μm, such as in the range of40-600 μm, such as in the range of 50-500 μm, such as in the range of100-400 μm, such as in the range of 200-300 μm, such as in the range of300-600 μm, such as in the range of 300-400 μm, such as in the range of400-600 μm or such as in the range of 500-600 μm, prior to step a)above.

In another embodiment, the particle size distribution of the activepharmaceutical ingredient (the fumaric acid ester(s)) is such that 0-5%of the particles have a particle size >500 μm and 45-53% of theparticles have a particle size >250 μm, prior to step a) above. In avariant hereof 7-15% of the particles have a particle size <100 μm,prior to step a) above.

In another embodiment, the particle size distribution of the activepharmaceutical ingredient (the fumaric acid ester(s)) is such that 0-7%of the particles have a particle size >500 μm and 42-59% of theparticles have a particle size >250 μm, prior to step a) above. In avariant hereof 3-12% of the particles have a particle size <100 μm,prior to step a) above.

In another embodiment, the particle size distribution of the activepharmaceutical ingredient (the fumaric acid ester(s)) is such that 0-10%of the particles have a particle size >500 μm and 40-65% of theparticles have a particle size >250 μm, prior to step a) above. In avariant hereof 2-10% of the particles have a particle size <100 μm,prior to step a) above.

In an embodiment of the invention the mean particle size of the activepharmaceutical ingredient (the fumaric acid ester(s)) is reduced, e.g.by sieving or milling, wherein said sieving or milling is performedproducing a minimum amount of heat. Thereby any sublimation of theactive pharmaceutical ingredient is minimised or reduced and anenergy-efficient process is obtained, mitigating loss of API, thusreducing cost as well as improving environmental and workers' safety.The sieving or milling may take place as a single sieving or millingstep or may optionally be repeated several times to obtain the requiredparticle distribution. In one embodiment of the invention, the sievingor milling takes place as a two-step process. In one embodiment of theinvention, where the sieving or milling is performed as several steps anagent for reducing agglomeration is added in between the steps.

Without being bound by theory the present inventors believe that theactive pharmaceutical ingredient (the fumaric acid ester(s)) having aparticle size distribution in the above ranges results in a slower invitro dissolution and thereby enables the use of a lower amount ofrate-controlling agent compared to a formulation having a particle sizedistribution with a higher particle size e.g. such that more than 10% ofthe particles have a particle size >500 μm and/or more than 65% of theparticles have a particle size >250 μm.

In one aspect, the lower amount of rate-controlling agent enablesmanufacture of a tablet with a high drug load such as at least 40%, 45%,50%, 55%, or 60% active pharmaceutical ingredient based on the totaltablet weight.

In an embodiment of the invention step b) is performed in a fluid bedgranulator.

Another aspect of the invention is a method for preparing theformulation according to the invention, comprising the steps of:

-   -   a) Dissolving (or suspending) a rate-controlling agent in the        form of a polymeric matrix material in water to obtain an        aqueous suspension thereof;    -   b) Spraying said aqueous suspension on granules of a fumaric        acid ester for a period of time sufficient to obtain a uniform        coating thereon;    -   c) Drying the granules obtained;    -   d) Optionally sieving or milling said granules;    -   e) Blending of any pharmaceutically acceptable excipients and        additives in a manner known per se to obtain a tablet        formulation;    -   f) Optionally film and/or enteric coating of said tablet        formulation in a manner known per se;

wherein any of or all of the above steps are performed at a temperatureto allow a product temperature not exceeding 45° C. In an embodiment ofthe invention any of or all of the above steps are performed at atemperature to allow a product temperature not exceeding 40° C., such asnot exceeding 35° C., such as not exceeding 30° C. Thereby anysublimation of the active pharmaceutical ingredient is minimised orreduced and an energy-efficient process is obtained, mitigating loss ofAPI, thus reducing cost as well as improving environmental and workers'safety.

In an embodiment of the invention the fumaric acid ester is micronizedto obtain a particle size, wherein at least 90% of the particles have aparticle size of at most 50 μm, such as at most 30 μm, such as at most10 μm, prior to step b) above.

In another embodiment, the mean particle size of the activepharmaceutical ingredient (the fumaric acid ester(s)) is reduced, e.g.by sieving or milling, wherein at least 90% of the particles have aparticle size of at most 800 μm, such as at most 600 μm, such as at most500 μm, such as at most 400 μm, such as at most 200 μm, prior to step b)above.

In an embodiment of the invention step b) is performed in a fluid bedgranulator.

Another embodiment of the invention is a method for preparing theformulation according to the invention, comprising the steps of:

-   -   a) Optionally sieving or milling crystals of fumaric acid ester;    -   b) Blending of said crystals of fumaric acid ester, optionally a        rate-controlling agent in the form of a polymeric matrix        material, and any pharmaceutically acceptable excipients and        additives by direct compression to obtain a tablet formulation;    -   c) Optionally film and/or enteric coating of said tablet        formulation in a manner known per se;

wherein any of or all of the above steps are performed at a temperatureto allow a product temperature not exceeding 45° C. In an embodiment ofthe invention any of or all of the above steps are performed at atemperature to allow a product temperature not exceeding 40° C., such asnot exceeding 35° C., such as not exceeding 30° C. Thereby anysublimation of the active pharmaceutical ingredient is minimised orreduced and an energy-efficient process is obtained, mitigating loss ofAPI, thus reducing cost as well as improving environmental and workers'safety.

Another embodiment of the invention is a method for preparing theformulation according to the invention, comprising the steps of:

-   -   a) Optionally sieving or milling crystals of fumaric acid ester;    -   b) Blending said crystals of fumaric acid ester with any        pharmaceutically acceptable excipients and optionally a        rate-controlling agent in the form of a polymeric matrix        material in a manner known per se to obtain a tablet        formulation;    -   c) Roller compaction of this blend and sieving/milling thereof        in order to obtain granules;    -   d) Admixing of any further pharmaceutically acceptable        excipients to the granules to obtain a final mix ready for        tabletting;    -   e) Compression to tablets;    -   f) Optionally film and/or enteric coating of said tablets.

In an embodiment of the invention the fumaric acid ester is preblendedwith one or more pharmaceutically acceptable excipients before step a)above.

The stability of the formulations according to the invention may bedetermined by measuring the initial in vitro dissolution profile of thetablets and the in vitro dissolution profile after different periods ofstorage and comparing the in vitro dissolution profiles obtained. In anembodiment of the invention the tablets are stable for at least 6months, such as at least 9 months, such as at least 12 months, such asat least 18 months, such as at least 24 months. The stability of theformulations according to the invention may also be determined bystandardized methods for measuring any changes in for example assay,colour or degradation products.

In an embodiment of the invention, stability of a formulation can bedefined by objective criteria, such as e.g. a certain maximum change ofthe amount of API released at a predetermined time point during astandardized in vitro dissolution test, when comparing the initialtesting time point to testing at a later point in time. In an embodimentof the invention, the amount of the API released from the formulationstored under ICH conditions (such as 25 degrees C./60% RH, such as 30degrees C./65% RH, such as 40 degrees C./75% RH) for a certain period oftime (such as at least 1 month, such as at least 3 months, such as atleast 6 months, such as at least 9 months, such as at least 12 months)c.f. the initial time point (time=0, set down of stability testing)—whensubjected to an in vitro dissolution test employing 0.1 N hydrochloricacid as dissolution medium during the first 2 hours of the test and then0.05 M phosphate buffer pH 6.8 as dissolution medium—is as follows:

1 hour after start of the test, a difference of less than 10 percentagepoints, such as less than 9 percentage points, such as less than 8percentage points, such as less than 6 percentage points, such as lessthan 4 percentage points, such as less than 2 percentage points, such asless than 1 percentage point in the amount of the active pharmaceuticalingredient released from the formulation is observed, and/or

2 hours after start of the test, a difference of less than 10 percentagepoints, such as less than 9 percentage points, such as less than 8percentage points, such as less than 6 percentage points, such as lessthan 4 percentage points, such as less than 2 percentage points, such asless than 1 percentage point in the amount of the active pharmaceuticalingredient released from the formulation is observed, and/or

3 hours after start of the test, a difference of less than 10 percentagepoints, such as less than 9 percentage points, such as less than 8percentage points, such as less than 6 percentage points, such as lessthan 4 percentage points, such as less than 2 percentage points, such asless than 1 percentage point in the amount of the active pharmaceuticalingredient released from the formulation is observed, and/or

4 hours after start of the test, a difference of less than 10 percentagepoints, such as less than 9 percentage points, such as less than 8percentage points, such as less than 6 percentage points, such as lessthan 4 percentage points, such as less than 2 percentage points, such asless than 1 percentage point in the amount of the active pharmaceuticalingredient released from the formulation is observed, and/or

5 hours after start of the test, a difference of less than 10 percentagepoints, such as less than 9 percentage points, such as less than 8percentage points, such as less than 6 percentage points, such as lessthan 4 percentage points, such as less than 2 percentage points, such asless than 1 percentage point in the amount of the active pharmaceuticalingredient released from the formulation is observed.

In an embodiment the pharmaceutical formulation according to theinvention is for use for the treatment of psoriasis, psoriaticarthritis, neurodermatitis, inflammatory bowel disease, such as Crohn'sdisease and ulcerative colitis, polyarthritis, multiple sclerosis (MS),juvenile-onset diabetes mellitus, Hashimoto's thyroiditis, Grave'sdisease, SLE (systemic lupus erythematosus), Sjögren's syndrome,Pernicious anemia, Chronic active (lupoid) hepatitis, Rheumatoidarthritis (RA), lupus nephritis, myasthenia gravis, uveitis, refractoryuveitis, vernal conjunctivitis, pemphigus vulgaris, scleroderma, opticneuritis, pain such as radicular pain, pain associated withradiculopathy, neuropathic pain or sciatica/sciatic pain, organtransplantation (prevention of rejection), sarcoidosis, necrobiosislipoidica or granuloma annulare.

An embodiment is the use of a pharmaceutical formulation according tothe invention for the preparation of a medicament for the treatment ofpsoriasis, psoriatic arthritis, neurodermatitis, inflammatory boweldisease, such as Crohn's disease and ulcerative colitis, polyarthritis,multiple sclerosis (MS), juvenile-onset diabetes mellitus, Hashimoto'sthyroiditis, Grave's disease, SLE (systemic lupus erythematosus),Sjögren's syndrome, Pernicious anemia, Chronic active (lupoid)hepatitis, Rheumatoid arthritis (RA), lupus nephritis, myastheniagravis, uveitis, refractory uveitis, vernal conjunctivitis, pemphigusvulgaris, scleroderma, optic neuritis, pain such as radicular pain, painassociated with radiculopathy, neuropathic pain or sciatica/sciaticpain, organ transplantation (prevention of rejection), sarcoidosis,necrobiosis lipoidica or granuloma annulare.

Another embodiment of the invention is a method of treating psoriasis,psoriatic arthritis, neurodermatitis, inflammatory bowel disease, suchas Crohn's disease and ulcerative colitis, polyarthritis, multiplesclerosis (MS), juvenile-onset diabetes mellitus, Hashimoto'sthyroiditis, Grave's disease, SLE (systemic lupus erythematosus),Sjögren's syndrome, Pernicious anemia, Chronic active (lupoid)hepatitis, Rheumatoid arthritis (RA), lupus nephritis, myastheniagravis, uveitis, refractory uveitis, vernal conjunctivitis, pemphigusvulgaris, scleroderma, optic neuritis, pain such as radicular pain, painassociated with radiculopathy, neuropathic pain or sciatica/sciaticpain, organ transplantation (prevention of rejection), sarcoidosis,necrobiosis lipoidica or granuloma annulare, which method comprisesadministering orally to a patient in need thereof an effective dosage ofa pharmaceutical formulation according to the invention.

In an embodiment of the invention the formulation according to theinvention is for use in the treatment of psoriasis.

In an embodiment of the invention the formulation according to theinvention is for use in the treatment of psoriatic arthritis.

In an embodiment of the invention the formulation according to theinvention is for use in the treatment of multiple sclerosis orrelapsing-remitting multiple sclerosis.

In an embodiment of the invention the formulation according to theinvention is for use in the the treatment of rheumatoid arthritis.

It is to be understood that this invention is not limited to particularembodiments described, as such may, of course, vary. It is also to beunderstood that the terminology used herein is for the purpose ofdescribing particular embodiments only, and is not intended to belimiting, since the scope of the present invention will be limited onlyby the appended claims. Where a range of values is provided, it isunderstood that each intervening value, to the tenth of the unit of thelower limit unless the context clearly dictates otherwise, between theupper and lower limit of that range and any other stated or interveningvalue in that stated range is encompassed within the invention. Theupper and lower limits of these smaller ranges may independently beincluded in the smaller ranges and are encompassed within the invention,subject to any specifically excluded limit in the stated range. Wherethe stated range includes one or both of the limits, ranges excludingeither or both of those included limits are also included in theinvention. Unless defined otherwise, all technical and scientific termsused herein have the same meaning as commonly understood by one ofordinary skill in the art to which this invention belongs. Although anymethods and materials similar or equivalent to those described hereincan also be used in the practice or testing of the present invention,the preferred methods and materials are described. All publicationsmentioned herein are incorporated herein by reference to disclose anddescribe the methods and/or materials in connection with which thepublications are cited. It must be noted that as used herein and in theappended claims, the singular forms “a”, “an”, and “the” include pluralreferents unless the context clearly dictates otherwise. The patents andpublications discussed herein are provided solely for their disclosureprior to the filing date of the present application. Nothing herein isto be construed as an admission that the present invention is notentitled to antedate such patent or publication by virtue of priorinvention. Further, the dates of publication provided may be differentfrom the actual publication dates which may need to be independentlyconfirmed. As will be apparent to those of skill in the art upon readingthis disclosure, each of the individual embodiments described andillustrated herein has discrete components and features which may bereadily separated from or combined with the features of any of the otherseveral embodiments without departing from the scope or spirit of thepresent invention. The figures shown herein are not necessarily drawn toscale, with some components and features being exaggerated for clarity.

Although the foregoing invention has been described in some detail byway of illustration and example for purposes of clarity ofunderstanding, it is readily apparent to those of ordinary skill in theart in light of the teachings of this invention that certain changes andmodifications may be made thereto without departing from the spirit orscope of the appended claims.

EXAMPLES

During the carrying out of all the following steps in examples 1-24 and26-42 necessary precautions are taken (protective clothing with externalair supply, double gloves, arm covers, breathing mask, etc.).

Example 1

Preparation of Core Tablets

540.5 g of micronized dimethyl fumarate (mean particle size 10 μm) and31.5 g hydroxypropyl cellulose HPC-SL was suspended in 1716 g purifiedwater. The suspension was sprayed over app. 2 hours onto 405.5 gGranulac®140 lactose placed in the basket of a fluid bed granulator. Thegranules were dried for 5 minutes. A seal coat was applied by spraying asolution of 22.5 g HPC-SL in 2265.5 g purified water over app. 2 hours.The product temperature never exceeded 35° C. Different batches wereblended and sieved through a 1.1 mm sieve.

183.3 g of the dried, sieved granules were blended with 58.7 gspray-dried lactose (FlowLac® 100) with a barrel blender at 30 rpm over15 minutes. Finally, 2.4 g magnesium stearate was added and blended overadditional 10 minutes at 30 rpm. The final blend was pressed intobiconvex tablets with a diameter of 10 mm and a weight of 375 mg.

Example 2

Preparation of Core Tablets

540.5 g of non-micronized dimethyl fumarate and 405.5 g Granulac® 140were placed in the basket of a fluid bed granulator. 62.1 ghydroxypropyl cellulose HPC-SL was dissolved by stirring in 3043 gpurified water and sprayed on DMF over 2.5 hours. The granules weredried over 4 minutes at 29° C. and sieved through a 1.1 mm sieve. Theproduct temperature never exceeded 30° C.

135 g of the dried granules were blended with 30.4 g spray-dried lactose(FlowLac® 100), 24.4 g HPC-SL and 0.3 g Aerosil with a barrel blender at30 rpm over 15 minutes. Finally, 1.8 g magnesium stearate was added andblended over additional 10 minutes at 30 rpm. The final blend waspressed into biconvex tablets with a diameter of 10 mm and a weight of315.5 mg.

Example 3

Preparation of Core Tablets

621.5 g of non-micronized dimethyl fumarate (mean particle size 500 μm)was suspended in 1793.5 g purified water and stirred with anUltra-turrax for 5 hours to reduced particle size. Then 36.2 ghydroxypropyl cellulose HPC-SL was added. The suspension was sprayedover app. 2 hours onto 405.5 g Granulac® 140 placed in the basket of afluid bed granulator. The granules were dried for 5 minutes. Hereafter aseal coat prepared from 26.3 g HPC-SL in 2605 g purified water wasapplied by spraying the solution over app. 2 hours onto the granules.The product temperature never exceeded 30° C.

183.3 g of the dried granules were blended with 58.7 g spray-driedlactose (FlowLacd® 100) and 0.5 g Aerosil with a barrel blender at 30rpm over 15 minutes. Finally, 2.2 g magnesium stearate was added andblended over additional 10 minutes at 30 rpm. The final blend waspressed into biconvex tablets with a diameter of 10 mm and a weight of375.4 mg.

Example 4

Preparation of Core Tablets

1200 g of non-micronized dimethyl fumarate was placed in the basket of afluid bed granulator. 75 g hydroxypropyl cellulose HPC-SL was dissolvedby stirring in 2925 g purified water and sprayed on DMF over app. 2.5hours until 70 g HPC was sprayed. The granules were dried over 4 minutesat 29° C. and sieved through a 1.1 mm sieve. The product temperaturenever exceeded 30° C.

378.2 g of the dried granules were blended with 400.6 g spray-driedlactose (FlowLac® 100), 14.6 g HPC-SL and 0.9 g Aerosil with a barrelblender at 30 rpm over 15 minutes. Finally, 5.8 g magnesium stearate wasadded and blended over additional 10 minutes at 30 rpm. The final blendwas pressed into biconvex tablets with a diameter of 8 mm and a weightof 275 mg.

Example 5

Film coating of core tablets according to example 4

Film Coating:

For film coating of 800 g core tablets a 15% suspension of Opadry wasprepared by adding 36 g Opadry to 204 g purified water. App. 66% of thissuspension was sprayed onto the core tablets over 35 minutes in a fluidbed chamber. The product temperature never exceeded 40° C. The coatingprocess was followed by a drying period of 16 minutes at 30° C.

Example 6

Film and enteric coating of core tablets according to example 4

Film Coating

Film coating was done with 800 g core tablets. A 15% suspension ofOpadry was prepared by adding 18 g Opadry to 102 g purified water. App.66% of this suspension was sprayed onto the core tablets over 20 minutesin a fluid bed chamber. The product temperature never exceeded 40° C.The coating process was followed by a drying period of 9 minutes at 30°C.

Enteric Coating

1 kg gastric acid-resistant coating fluid was prepared by heating 350 mlpurified water to 70-80° C., adding 20 g triethyl citrate, 3 g glycerylmonostearate (Cutina GMS V), 1 g Tween 80 and stirring with theUltraTurrax for 10 minutes to achieve a homogenous mixture. 427.8 gpurified water was added and the mixture was stirred with a propellerstirrer until the emulsion had reached room temperature. This emulsionwas then added slowly to 210 g of a Eudragit L30 D 55 dispersion.Approximately 66% of the resulting gastric acid-resistant coating fluidwas sprayed on 780 g film coated tablets in a fluid bed chamber at atemperature of 30° C. over app. 2.5 hours. A drying period at 30° C. for30 minutes and a curing period at 35° C. for additional 30 minutesfollowed.

Example 7

Enteric coating of core tablets according to example 4

Enteric Coating

1 kg gastric acid-resistant coating fluid was prepared and sprayed oncore tablets as disclosed in example 6.

Example 8

Granules were prepared as disclosed in example 4.

416 g of the dried granules were blended with 360.8 g spray-driedlactose (FlowLac® 100), 16 g HPC-SL and 1 g Aerosil with a barrelblender at 30 rpm over 15 minutes. Finally, 6.4 g magnesium stearate wasadded and blended over additional 10 minutes at 30 rpm. The final blendwas pressed into biconvex tablets with a diameter of 8 mm and a weightof 250 mg.

Example 9

Film coating of core tablets according to example 8

Film Coating

Film coating was carried out as disclosed in example 5.

Example 10

Film and enteric coating of core tablets according to example 8

Film Coating

Film coating was done with 800 g core tablets as disclosed in example 6.

Enteric Coating

1 kg gastric acid-resistant coating fluid was prepared and applied asdisclosed in example 6.

Example 11

Granules were prepared as disclosed in example 4.

404.5 g of the dried granules are blended with 272.9 g spray driedlactose (FlowLac 100®), 15.5 g HPC-SL and 0.9 g Aerosil with a barrelblender at 30 rpm over 15 minutes. Finally, 6.2 g Magnesium stearate isadded and blended over additional 10 minutes at 30 rpm. The final blendis pressed into biconvex tablets with a diameter of 8 mm and a weight of225 mg.

Example 12

Film coating of core tablets is performed according to example 11

Film Coating

For film coating 800 g core tablets are coated as disclosed in example5. To have 800 g tablets available for coating active tablets areblended with colored placebo.

Example 13

Film and enteric coating of core tablets according to example 11

Film Coating

Film coating was done with 800 g core tablets as disclosed in example 5.To have 800 g tablets available for coating active tablets were blendedwith colored placebo.

Enteric Coating

1 kg gastric acid-resistant coating fluid was prepared as applied asdisclosed in example 6.

Example 14

Granules were prepared as in example 4.

130 g of the dried granules were blended with 52.7 g spray-dried lactose(FlowLac® 100), 40 g HPC-SL and 0.3 g Aerosil with a barrel blender at30 rpm over 15 minutes. Finally, 2.0 g magnesium stearate was added andblended over additional 10 minutes at 30 rpm. The final blend waspressed into biconvex tablets with a diameter of 8 mm and a weight of225 mg.

Example 15

Film coating of core tablets according to example 14

Film Coating

For film coating 800 g tablets were coated as disclosed in example 5. Tohave 800 g tablets available for coating active tablets were blendedwith colored placebo.

Example 16

Film and enteric coating of core tablets according to example 14

Film Coating

Film coating was done with 800 g core tablets. Therefore the APIcontaining tablets were blended with colored placebo to obtain therequired amount. A 15% suspension of Opadry was prepared and applied asdisclosed in example 6.

Enteric Coating

1 kg gastric acid-resistant coating fluid was prepared and applied asdisclosed in example 6.

The dissolution profile of film and enteric coated tablets according tothis example was obtained in accordance with a United StatesPharmacopeia (USP) in vitro test. The test was carried out at 37° C.using a paddle dissolution apparatus at 100 rpm employing 0.1 Nhydrochloric acid as dissolution medium during the first 2 hours of thetest and then followed by 0.05 M phosphate buffer pH 6.8 as dissolutionmedium for the remaining test period. The result appears from FIG. 1.

Example 17

1.2 kg dimethyl fumarate was sieved through a 700 μm sieve and placed inthe basket of a fluid bed granulator. 70.6 g polymer hydroxypropylcellulose HPC-SL was dissolved by stirring in 2753 g purified water andsprayed on the DMF over 2.5 to 3 hours. The granules were dried for 3minutes at 29° C. Several batches were blended and sieved through a 800μm sieve.

1730.7 g of the dried and additional through 500 μm sieved granules wereblended with 781.3 g granulated lactose (Tablettose® 100), 66.7 g HPC-SLand a pre-blend of Aerosil® and Tablettose® with a barrel blender at 20rpm over 15 minutes. The pre-blend was prepared in a polyethylene bag of4 g colloidal silicic acid (Aerosil®) and 390.6 g Tablettose® and sievedthrough 500 μm. Finally, 26.7 g magnesium stearate was added. The finalblend was pressed into biconvex tablets with a diameter of 8 mm and aweight of 225 mg.

Example 18

Film and enteric coating of core tablets according to example 17

Film Coating

For film coating of 800 g core tablets a 15% suspension of Opadry wasprepared by adding 18 g Opadry to 102 g purified water. App. 66% of thissuspension was sprayed onto the core tablets over 20 minutes in a fluidbed chamber. The product temperature never exceeded 40° C. The coatingprocess was followed by a drying period of 9 minutes at 30° C.

Enteric Coating

1 kg gastric acid-resistant coating fluid was prepared by heating 350 mlpurified water to 70-80° C., adding 9.5 g triethyl citrate, 1.9 gglyceryl monostearate (Cutina GMS V), 0.7 g Tween 80 and stirring withthe UltraTurrax for 10 minutes to achieve a homogenous mixture. 427.8 gpurified water was added and the mixture was stirred with a propellerstirrer until the emulsion had reached room temperature. This emulsionwas then added slowly to 210 g of a Eudragit® L30 D 55 dispersion.Approximately 66% of the resulting gastric acid-resistant coating fluidwas sprayed on 780 g film-coated tablets in a fluid bed chamber.

The dissolution profile of film and enteric coated tablets according tothis example was obtained in accordance with an in vitro dissolutiontest as described in example 16 employing 0.1 N hydrochloric acid asdissolution medium during the first 2 hours of the test and then 0.05 Mphosphate buffer pH 6.8 as dissolution medium appears from FIG. 1.

Example 19

1.2 kg dimethyl fumarate was sieved through a 700 μm sieve and placed inthe basket of a fluid bed granulator. 70.6 g hydroxypropyl celluloseHPC-SL was dissolved by stirring in 2753 g purified water and sprayed onthe DMF over 2.5 to 3 hours. The granules were dried for 3 minutes at29° C. and sieved through a 500 μm sieve.

964 g of the dried, sieved granules were blended with 565.5 g granulatedlactose (Tablettose® 100), 37.4 g HPC-SL and a pre-blend of Aerosil® andTablettose® with a barrel blender at 20 rpm over 15 minutes. Thepre-blend was prepared in a polyethylene bag of 2.3 g colloidal silicicacid (Aerosil®) and 282.7 g Tablettose® and sieved through 500 μm aswell. Finally, 14.9 g magnesium stearate was added. The final blend waspressed into biconvex tablets with a diameter of 8 mm and a weight of250 mg.

Example 20

Film and enteric coating of core tablets according to example 19

Film Coating

For film coating of 800 g core tablets a 15% suspension of Opadry isprepared and applied as disclosed in example 18.

Enteric Coating

1 kg gastric acid-resistant coating fluid was prepared by heating 350 mlpurified water to 70-80° C., adding 9.5 g triethyl citrate, 1.9 gglyceryl monostearate (Cutina GMS V), 0.7 g Tween 80 and stirring withthe UltraTurrax for 10 minutes to achieve a homogenous mixture. 427.8 gpurified water was added and the mixture was stirred with a propellerstirrer until the emulsion had reached room temperature. This emulsionwas then added slowly to 210 g of a Eudragit® L30 D 55 dispersion.Approximately 66% of the resulting gastric acid-resistant coating fluidwas sprayed on 780 g film coated tablets in a fluid bed chamber at atemperature of 30° C. over app. 2.5 hours. A drying period at 30° C. for30 minutes and a curing period at 35° C. for additional 30 minutesfollowed.

The dissolution profile of film and enteric coated tablets according tothis example was obtained in accordance with an in vitro dissolutiontest as described in example 16 employing 0.1 N hydrochloric acid asdissolution medium during the first 2 hours of the test and then 0.05 Mphosphate buffer pH 6.8 as dissolution medium appears from FIG. 1.

Example 21

1.2 kg dimethyl fumarate was sieved through a 700 μm sieve and placed inthe basket of a fluid bed granulator. 70.6 g hydroxypropyl celluloseHPC-SL was dissolved by stirring in 2753 g purified water and sprayed onthe DMF over 2.5 to 3 hours. The granules were dried for 3 minutes at29° C. Several batches were blended and sieved through 800 μm.

1416 g of the dried and additional through 500 μm sieved granules wereblended with 1002.9 g granulated lactose (Tablettose® 100), 54.6 gHPC-SL and a pre-blend of Aerosil® and Tablettose® with a barrel blenderat 20 rpm over 15 minutes. The pre-blend was prepared in a polyethylenebag of 3.3 g colloidal silicic acid (Aerosil®) and 501.4 g Tablettose®and sieved through 500 μm. Finally, 21.8 g magnesium stearate was added.The final blend was pressed into biconvex tablets with a diameter of 8mm and a weight of 275 mg.

Example 22

Film and enteric coating of core tablets according to example 21

Film Coating

For film coating of 800 g core tablets a 15% suspension of Opadry wasprepared and applied as disclosed in example 18.

Enteric Coating:

1 kg gastric acid-resistant coating fluid was prepared by heating 350 mlpurified water to 70-80° C., adding 9.5 g triethyl citrate, 1.9 gglyceryl monostearate (Cutina GMS V), 0.7 g Tween 80 and stirring withthe UltraTurrax for 10 minutes to achieve a homogenous mixture. 427.8 gpurified water was added and the mixture was stirred with a propellerstirrer until the emulsion had reached room temperature. This emulsionwas then added slowly to 210 g of a Eudragit® L30 D 55 dispersion.Approximately 66% of the resulting gastric acid-resistant coating fluidwas sprayed on 780 g film coated tablets in a fluid bed chamber at atemperature of 30° C. over app. 2.5 hours. A drying period at 30° C. for30 minutes and a curing period at 35° C. for additional 30 minutesfollowed.

The dissolution profile of film and enteric coated tablets according tothis example was obtained in accordance with an in vitro dissolutiontest as described in example 16 employing 0.1 N hydrochloric acid asdissolution medium during the first 2 hours of the test and then 0.05 Mphosphate buffer pH 6.8 as dissolution medium appears from FIG. 1.

Example 23

Film coating of core tablets according to example 18

Film Coating

For film coating of 800 g core tablets a 15% suspension of Opadry wasprepared by adding 36 g Opadry to 204 g purified water. App. 66% of thissuspension was sprayed onto the core tablets over 35 minutes in a fluidbed chamber. The product temperature never exceeded 40° C. The coatingprocess was followed by a drying period of 16 minutes at 30° C.

The dissolution profile of film coated tablets according to this examplesubjected to an in vitro dissolution test employing 0.1 N hydrochloricacid as dissolution medium during the first 2 hours of the test and then0.05 M phosphate buffer pH 6.8 as dissolution medium appears from FIG.2.

Example 24

18 g of pure DMF (particle sice 250-500 μm) were blended with 6.3 gHPC-SL, 9.1 g spray dried lactose (FlowLac® 100) and 0.045 g Aerosil.Finally, 0.3 g magnesium stearate was added and blended. The final blendwas pressed into biconvex tablets with a diameter of 8 mm and a weightof 225 mg.

Example 25

The study was a single center study, following an open-label,randomized, crossover design to investigate the plasma concentrations,pharmacokinetics, safety and tolerability of pharmaceutical formulationsaccording to the invention c.f. the marketed formulation Fumaderm® asreference. The tablets were administered as a single oral dose of 240 mg(2 tablets containing 120 mg each) in each treatment period according torandomization to 20 healthy, male Caucasian subjects. The study wasdivided into four treatment periods (Treatment Period 1, 2, 3 and 4),which were separated by a wash-out phase of at least 7 days.

Subjects were screened for eligibility at least 21 to 2 days beforefirst administration including: check of inclusion/exclusion criteria;demographic data (including age, body height, body weight, body massindex (BMI), and ethnic origin); physical examination; complete medicalhistory; 12-lead electrocardiogram (ECG); vital signs (blood pressure(BP), pulse rate (PR), and body temperature (BT)); clinical laboratoryparameters (hematology, serum biochemistry, and urinalysis);documentation of concomitant illness and medication.

At each of the four treatment periods, subjects came to the Study Sitein the evening of Day −1 and remained there until the 24-hour bloodsample for PK analysis was drawn and all safety measurements wereperformed (=morning of Day 2).

The subjects fasted overnight. A single oral dose (of two tablets) ofone of the formulations according to the invention (Examples 18, 20 or22), or two enteric-coated tablets of the reference medication Fumaderm®each containing 120 mg dimethyl fumarate (total dose 240 mg dimethylfumarate) were administered on Day 1 (according to randomization).Administration was done to subjects who were in fasting conditiontogether with 240 ml tap water. Between each administration, a wash-outinterval of at least 7 days was maintained.

The following assessments/measurements were performed:

Blood sampling was performed for the determination of plasmaconcentrations and PK-parameters prior to, and at pre-scheduled timespost dosing.

Adverse events were documented in detail throughout the study.

Urine was collected prior to and at pre-scheduled times post dosing.

A follow-up examination was performed at least 7 days after the lastadministration (Treatment Period 4), including: physical examination;vital signs (BP, PR, and BT); body weight; 12-lead ECG; clinicallaboratory parameters (haematology, serum biochemistry, and urinalysis);documentation of concomitant medication and adverse events.

Example 26

Preparation of Core Tablets

Dimethyl fumarate was sieved through a hand screen of 500 μm. 29.3 g ofsieved dimethyl fumarate, 2.93 g of HPC-SL, 22.17 g of granulatedlactose (Tablettose® 100), 0.07 g of Aerosil® as well as 0.49 g ofmagnesium stearate were blended for 10 minutes. The blend was pressedinto biconvex tablets with a diameter of 8 mm and a weight of 225 mg.

Example 27a

Preparation of Core Tablets

Dimethyl fumarate was sieved through a hand screen of 500 μm. 500 g ofsieved dimethyl fumarate, 48 g of HPC-SL, 447 g of spray dried lactose(FlowLac® 100) and 1.2 g Aerosil® were blended with a barrel blender for15 minutes at 20 rpm. Finally, 4 g of magnesium stearate was added andthe mixture blended again for 10 min at 20 rpm. The blend was pressedinto biconvex tablets with a diameter of 8 mm and a weight of 250 mg.

Enteric Coating

A gastric acid-resistant coating fluid was prepared by heating 247 g ofpurified water to 70-80° C., then 9 g of triethyl citrate, 1.8 g ofglyceryl monostearate (Cutina GMS V), and 0.72 g of Tween 80 was addedand stirred with the UltraTurrax for 10 minutes to achieve a homogenousmixture. 495 g of purified water was added and the mixture was stirredwith a propeller stirrer until the emulsion had reached roomtemperature. This emulsion was then added slowly to 200 g of EudragitL30 D 55 dispersion. The resulting gastric acid-resistant coating fluidwas sprayed on the core tablets directly in a perforated drum coater.The amount of solution sprayed onto the tablets was 1.5% solids w/wresulting in a weight increase of the coated tablets compared to coretablets of 1%.

Example 27b

Preparation of core tablets was performed as described in Example 27a.

Enteric Coating

A gastric acid-resistant coating fluid was prepared by heating 247 g ofpurified water to 70-80° C., then 9 g of triethyl citrate, 1.8 g ofglyceryl monostearate (Cutina GMS V), and 0.72 g of Tween 80 was addedand stirred with the UltraTurrax for 10 minutes to achieve a homogenousmixture. 495 g of purified water was added and the mixture was stirredwith a propeller stirrer until the emulsion had reached roomtemperature. This emulsion was then added slowly to 200 g of EudragitL30 D 55 dispersion. The resulting gastric acid-resistant coating fluidwas sprayed on the core tablets directly in a perforated drum coater.The amount of solution sprayed onto the tablets was 2.5% solids w/wresulting in a weight increase of the coated tablets compared to coretablets of 1.8%.

Example 28

Preparation of Core Tablets

Dimethyl fumarate was sieved through a hand screen of 500 μm. 500 gsieved dimethyl fumarate, 48 g of HPC-SL and 447 g of granulated lactose(Tablettose® 100) and 1.2 g Aerosil® were blended with a barrel blenderfor 15 minutes at 20 rpm. Finally, 4 g of magnesium stearate was addedand the mixture blended again for 10 min at 20 rpm. The blend waspressed into biconvex tablets with a diameter of 8 mm and a weight of250 mg.

Enteric Coating

A gastric acid-resistant coating fluid was prepared by heating 99 g ofpurified water to 70-80° C., then 10.1 g of triethyl citrate, 2.0 g ofglyceryl monostearate (Cutina GMS V), and 0.8 g of Tween 80 was addedand stirred with the UltraTurrax for 10 minutes to achieve a homogenousmixture. 198 g of purified water was added and the mixture was stirredwith a propeller stirrer until the emulsion had reached roomtemperature. This emulsion was then added slowly to 224 g of EudragitL30 D 55 dispersion. The resulting gastric acid-resistant coating fluidwas sprayed on the core tablets directly in a perforated drum coater.The solution was sprayed to a weight increase of the core tablets of 3%.

Example 29a

Preparation of Core Tablets

Dimethyl fumarate was milled through 1143 μm and 610 μm screens. 500 gsieved dimethyl fumarate, 48 g of HPC-SL and 447 g of granulated lactose(Tablettose® 100) and 1.2 g of Aerosil® were blended with a barrelblender for 15 minutes at 20 rpm. Finally, 4 g of magnesium stearate wasadded and the mixture blended again for 10 min at 20 rpm. The blend waspressed into biconvex tablets with a diameter of 8 mm and a weight of250 mg.

Enteric Coating

A gastric acid-resistant coating fluid was prepared by heating 247 g ofpurified water to 70-80° C., then 9 g of triethyl citrate, 1.8 g ofglyceryl monostearate (Cutina GMS V), and 0.72 g of Tween 80 was addedand stirred with the UltraTurrax for 10 minutes to achieve a homogenousmixture. 495 g of purified water was added and the mixture was stirredwith a propeller stirrer until the emulsion had reached roomtemperature. This emulsion was then added slowly to 200 g of EudragitL30 D 55 dispersion. The resulting gastric acid-resistant coating fluidwas sprayed on the core tablets directly in a perforated drum coater.The amount of Eudragit sprayed onto the tablets was 2.5% solids w/wresulting in a weight increase of the coated tablets compared to coretablets of 1.5%.

Example 29b

Preparation of core tablets was performed as described in Example 29a.

Enteric Coating

A gastric acid-resistant coating fluid was prepared by heating 247 g ofpurified water to 70-80° C., then 9 g of triethyl citrate, 1.8 g ofglyceryl monostearate (Cutina GMS V), and 0.72 g of Tween 80 was addedand stirred with the UltraTurrax for 10 minutes to achieve a homogenousmixture. 495 g of purified water was added and the mixture was stirredwith a propeller stirrer until the emulsion had reached roomtemperature. This emulsion was then added slowly to 200 g of EudragitL30 D 55 dispersion. The resulting gastric acid-resistant coating fluidwas sprayed on the core tablets directly in a perforated drum coater.The amount of Eudragit sprayed onto the tablets was 3.5% solids w/wresulting in a weight increase of the coated tablets compared to coretablets of 2%.

Example 30

Preparation of Core Tablets

2500 g of dimethyl fumarate was milled through 1575 μm and 813 μmscreens. Before the second milling step 6 g of Aerosil® was added. Theachieved particle size distribution was approx. 11%>500 μm, approx.70%>250 μm and approx. 7%<100 μm. The mean particle size was 358 μm.

The milled material was blended further with 240 g of HPC-SL and 2714 gof granulated lactose (Tablettose® 100) with a barrel blender for 15minutes at 20 rpm. Finally, 20 g of magnesium stearate was added and themixture blended again for 10 min at 20 rpm. The blend was pressed intobiconvex tablets with a diameter of 8 mm and a weight of 275 mg. Thecore tablets were optionally enteric coated as described in example 33a.

Example 31

Preparation of Core Tablets

2500 g of dimethyl fumarate was milled through 1575 μm and 813 μmscreens. Before the second milling step 6 g of Aerosil® was added. Theachieved particle size distribution was approx. 3%>500 μm, approx.65%>250 μm and approx. 6%<100 μm. The mean particle size was 290 μm.

The milled material was blended further with 240 g of HPC-SL and 2714 gof granulated lactose (Tablettose® 100) with a barrel blender for 15minutes at 20 rpm. Finally, 20 g of magnesium stearate was added and themixture blended again for 10 min at 20 rpm. The blend was pressed intobiconvex tablets with a diameter of 8 mm and a weight of 275 mg. Thecore tablets may be enteric coated as described in example 33a or b.

Example 32

Preparation of Core Tablets

2500 g of dimethyl fumarate was milled through 1575 μm and 813 μmscreens. Before the second milling step 6 g of Aerosil® was added. Theachieved particle size distribution was approx. 3%>500 μm, approx.5⁰%>250 μm and approx. 10%<100 μm. The mean particle size was 250 μm.

The milled material was blended further with 240 g of HPC-SL and 2714 gof granulated lactose (Tablettose® 100) with a barrel blender for 15minutes at 20 rpm. Finally, 20 g of magnesium stearate was added and themixture blended again for 10 min at 20 rpm. The blend was pressed intobiconvex tablets with a diameter of 8 mm and a weight of 275 mg. Thecore tablets were optionally enteric coated as described in example 33b.

Example 33a

Enteric Coating

A gastric acid-resistant coating fluid was prepared by heating 1193 g ofpurified water to 70-80° C., then 45 g of triethyl citrate, 13.5 g ofglyceryl monostearate (Cutina GMS V), and 5.4 g of Tween 80 was addedand stirred with the UltraTurrax for 10 minutes to achieve a homogenousmixture. 2385 g of purified water was added and the mixture was stirredwith a propeller stirrer until the emulsion had reached roomtemperature. This emulsion was then added slowly to 1500 g of EudragitL30 D 55 dispersion. The resulting gastric acid-resistant coating fluidwas sprayed on the core tablets directly in a perforated drum coater.The amount of Eudragit sprayed onto the tablets was 3.0% w/w resultingin a weight increase of the coated tablets compared to core tablets of2.5%.

Example 33b

Enteric Coating

A gastric acid-resistant coating fluid was prepared by heating 1193 g ofpurified water to 70-80° C., then 45 g of triethyl citrate, 13.5 g ofglyceryl monostearate (Cutina GMS V), and 5.4 g of Tween 80 was addedand stirred with the UltraTurrax for 10 minutes to achieve a homogenousmixture. 2385 g of purified water was added and the mixture was stirredwith a propeller stirrer until the emulsion had reached roomtemperature. This emulsion was then added slowly to 1500 g of EudragitL30 D 55 dispersion. The resulting gastric acid-resistant coating fluidwas sprayed on the core tablets directly in a perforated drum coater.The amount of Eudragit sprayed onto the tablets was 3.5% resulting in aweight increase of the coated tablets compared to core tablets of 3%.

Example 34

Preparation of Core Tablets

2500 g of dimethyl fumarate was milled through 1575 μm and 813 μmscreens. Before the second milling step 6 g Aerosil® was added. Theachieved particle size distribution was 8%>500 μm, 80%>250 μm and 0%<100μm. The mean particle size was 360 μm.

The milled material was blended further with 240 g of HPC-SL and 2234 gof granulated lactose (Tablettose® 100) with a barrel blender for 15minutes at 20 rpm. Finally, 20 g of magnesium stearate was added and themixture blended again for 10 min at 20 rpm. The blend was pressed intobiconvex tablets with a diameter of 8 mm and a weight of 250 mg. Thecore tablets may be enteric coated as described in example 33a or b.

Example 35

Preparation of Core Tablets

2500 g of dimethyl fumarate was milled through 1575 μm and 813 μmscreens. Before the second milling step 6 g Aerosil® was added. Theachieved particle size distribution was 6%>500 μm, 65%>250 μm and 6%<100μm. The mean particle size was 305 μm.

The milled material was blended further with 240 g of HPC-SL and 2234 gof granulated lactose (Tablettose® 100) with a barrel blender for 15minutes at 20 rpm. Finally, 20 g of magnesium stearate was added and themixture blended again for 10 min at 20 rpm. The blend was pressed intobiconvex tablets with a diameter of 8 mm and a weight of 250 mg. Thecore tablets may be enteric coated as described in example 33a or b.

Example 36

Preparation of Core Tablets

2500 g of dimethyl fumarate was milled through 1575 μm and 813 μmscreens. Before the second milling step 6 g Aerosil® was added. Theachieved particle size distribution was 3%>500 μm, 63%>250 μm and 6%<100μm. The mean particle size was 290 μm.

The milled material was blended further with 240 g of HPC-SL and 2234 gof granulated lactose (Tablettose® 100) with a barrel blender for 15minutes at 20 rpm. Finally, 20 g of magnesium stearate was added and themixture blended again for 10 min at 20 rpm. The blend was pressed intobiconvex tablets with a diameter of 8 mm and a weight of 250 mg. Thecore tablets may be enteric coated as described in example 33a or b.

Example 37

Preparation of Core Tablets

2500 g of dimethyl fumarate is milled through 1575 μm and 813 μmscreens. Before the second milling step 6 g of Aerosil® is added.

The milled material is blended further with 240 g of HPC-SL and 1714 gof granulated lactose (Tablettose® 100) with a barrel blender for 15minutes at 20 rpm. Finally, 20 g of magnesium stearate is added and themixture blended again for 10 min at 20 rpm. The blend is pressed intobiconvex tablets with a diameter of 8 mm and a weight of 225 mg. Thecore tablets may be enteric coated as described in example 33a or b.

Example 38

2.500 g of DMF is milled through 1575 μm and 813 μm screens. 240 g ofHPC-SL, 2.734 g of Tablettose 100 and 6 g of Aerosil is added andblended with the DMF. The blend is roller compacted and passed through a1 mm screen to obtain granules. 20 g of magnesium stearate is admixed toobtain a final mix ready for tabletting. Said mix is compressed totablets having a tablet weight of 275 mg. The core tablets may beenteric coated as described in example 33a or b.

Example 39

2.500 g of DMF is blended with 6 g of Aerosil and subsequently milledthrough 1575 μm and 813 μm screens. 240 g of HPC-SL and 2.734 g ofTablettose 100 is added and blended with the DMF and Aerosil. The blendis roller compacted and passed through a 1 mm screen to obtain granules.20 g of magnesium stearate is admixed to obtain a final mix ready fortabletting. Said mix is compressed to tablets having a tablet weight of275 mg. The core tablets may be enteric coated as described in example33a or b.

Example 40

2000 g dimethyl fumarate was milled through 1575 μm and 813 μm screens.Before the second milling step 4.8 g of Aerosil® was added.

475.3 g of the milled material was blended further with 519.8 g ofgranulated lactose (Tablettose® 100) with a barrel blender for 15minutes at 20 rpm. Finally, 3.8 g of magnesium stearate was added andthe mixture was blended again for 10 min at 20 rpm. The blend waspressed into biconvex tablets with a diameter of 8 mm and a weight of263 mg. The core tablets may be enteric coated as described in example33a or b.

Example 41

2000 g dimethyl fumarate was milled through 1575 μm and 813 μm screens.Before the second milling step 4.8 g of Aerosil® was added.

468.2 g of the milled material was blended further with 15 g HPC-SL and512 g of granulated lactose (Tablettose® 100) with a barrel blender for15 minutes at 20 rpm. Finally, 3.7 g of magnesium stearate was added andthe mixture was blended again for 10 min at 20 rpm. The blend waspressed into biconvex tablets with a diameter of 8 mm and a weight of267 mg. The core tablets may be enteric coated as described in example33a or b.

Example 42

2000 g dimethyl fumarate was milled through 1575 μm and 813 μm screens.Before the second milling step 4.8 g of Aerosil® was added.

500 g of the milled material was blended further with 32 g HPC-SL and562.8 g of granulated lactose (Tablettose® 100) with a barrel blenderfor 15 minutes at 20 rpm. Finally, 4 g of magnesium stearate was addedand the mixture was blended again for 10 min at 20 rpm. The blend waspressed into biconvex tablets with a diameter of 8 mm and a weight of250 mg. The core tablets may be enteric coated as described in example33a or b.

Example 43

A study as the one disclosed in example 25 was performed on tablets asdisclosed in examples 18 and 22 and compared with corresponding data forthe prior art formulation Fumaderm®. The results of the study are shownin Table I and Table II below.

TABLE I Coefficients of variation in % (CV). Example 18 Example 22Fumaderm ® AUC 22% 18% 38% C_(max) 34% 26% 49%

TABLE II Summary Table: Percentage of subjects with adverse effects/sideeffects after administration of formulation according to examples 18 and22, respectively, compared to administration of Fumaderm ® Afteradministration of After administration of formulation acc. to ex.formulation acc. to ex. 18 c.f. after 22 c.f. after Adverse effect/administration of administration of side effect Fumaderm ® Fumaderm ®Flushing 35% 65% GI related 50% 73% adverse effects Any adverse 50% 77%effect

The above results of the clinical trial shows (Table II) that the testedformulations have a markedly reduced frequency of adverse effectscombined with a lower variability (cf. Table I) compared to Fumaderm®.This example thus shows that the inventive formulations have anunexpectedly large reduction in variability in AUC and C_(max) vis-h-visthe prior art Fumaderm® formulation.

1.-46. (canceled)
 47. A method of treating psoriasis, psoriaticarthritis, neurodermatitis, inflammatory bowel disease, Crohn's disease,and ulcerative colitis, polyarthritis, multiple sclerosis,juvenile-onset diabetes mellitus, Hashimoto's thyroiditis, Grave'sdisease, systemic lupus erythematosus, Sjogren's syndrome, Perniciousanemia, Chronic active (lupoid) hepatitis, Rheumatoid arthritis, lupusnephritis, myasthenia gravis, uveitis, refractory uveitis, vernalconjunctivitis, pemphigus vulgaris, scleroderma, optic neuritis,radicular pain, pain associated with radiculopathy, neuropathic pain,sciatica/sciatic pain, organ transplantation rejection, sarcoidosis,necrobiosis lipoidica or granuloma annulare, which method comprisesadministering orally to a patient in need thereof an effective dosage ofa pharmaceutical formulation in the form of an erosion matrix tabletcomprising: a) a tablet core comprising i) 10% to 80% by weight of oneor more fumaric acid esters selected from di-(C₁-C₅)alkylesters offumaric acid and mono-(C₁-C₅)alkylesters of fumaric acid, or apharmaceutically acceptable salt thereof, as an active substance, andii) 1% to 50% by weight of one or more rate-controlling agents; and b)an enteric coating, wherein said enteric coating is applied at a levelof 1.5% to 3.5% by weight of the tablet core; wherein erosion of saiderosion matrix permits controlled or sustained release of said activesubstance.
 48. The method according to claim 47, which is a method fortreating psoriasis.
 49. The method according to claim 47, which is amethod for treating psoriatic arthritis.
 50. The method according toclaim 47, which is a method for treating multiple sclerosis.
 51. Themethod according to claim 47, which is a method for treating rheumatoidarthritis.
 52. The method according to claim 47, wherein the tablet corecomprises: i) 30% to 60% by weight of the one or more fumaric acidesters, and ii) 3% to 40% by weight of the one or more rate-controllingagents.
 53. The method according to claim 47, wherein the erosion matrixis a monolithic erosion matrix.
 54. The method according to claim 47,wherein the rate-controlling agent is a water-soluble polymer.
 55. Themethod according to claim 54, wherein the water-soluble polymer isselected from the group consisting of hydroxypropyl methyl cellulose,hydroxypropyl cellulose, methyl cellulose, and carboxymethyl cellulose.56. The method according to claim 55, wherein the water-soluble polymeris hydroxypropyl cellulose.
 57. The method according to claim 47,wherein the tablet core further comprises a binder.
 58. The methodaccording to claim 57, wherein the tablet core comprises: i) 40% to 60%by weight of one or more fumaric acid esters selected from the groupconsisting of di-(C₁-C₅)alkylesters of fumaric acid andmono-(C₁-C₅)alkylesters of fumaric acid, and a pharmaceuticallyacceptable salt thereof, as an active substance, ii) 4% to 6% by weightof a rate-controlling agent, and iii) 35% to 55% by weight of a binder.59. The method according to claim 47, wherein the fumaric acid ester isselected from the group consisting of dimethylfumarate, diethylfumarate,dipropylfumarate, dibutylfumarate, dipentylfumarate,methyl-ethylfumarate, methyl-propylfumarate, methyl-butylfumarate,methyl-pentylfumarate, monomethylfumarate, monoethylfumarate,monopropylfumarate, monobutylfumarate, and monopentylfumarate, or apharmaceutically acceptable salt thereof.
 60. The method according toclaim 59, wherein the tablet core comprises a pharmaceuticallyacceptable salt of a mono-(C₁-C₅)alkylester of fumaric acid as theactive substance.
 61. The method according to claim 47, wherein thetablet core comprises dimethylfumarate as the active substance.
 62. Themethod according to claim 47, wherein the tablet core comprisesmonomethylfumarate or a pharmaceutically acceptable salt thereof as theactive substance.
 63. The method according to claim 58, wherein thetablet core comprises: i) 40% to 55% by weight of dimethyl fumarate, ii)4% to 6% by weight of hydroxypropyl cellulose, and iii) 35% to 55% byweight of lactose.
 64. The method according to claim 47, wherein theerosion matrix does not contain a water-insoluble polymer.